Journal List > Korean J Physiol Pharmacol > v.22(1) > 1026228

Korean J Physiol Pharmacol. 2018 Jan;22(1):1-15. English.
Published online December 22, 2017.
Copyright © 2018 The Korean Physiological Society and The Korean Society of Pharmacology
Role of inflammasomes in inflammatory autoimmune rheumatic diseases
Young-Su Yi
Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28503, Korea.

Correspondence: Young-Su Yi. Email:
Received August 07, 2017; Revised October 19, 2017; Accepted November 01, 2017.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.

Keywords: Autoimmunity; Inflammasome; Inflammation; Macrophage; Rheumatic diseases


Inflammation, an innate immune response mediated mainly by macrophages, is a series of biological processes to protect the body from invading pathogens including bacteria, viruses, protozoans, and fungi. Inflammation is characterized by pain, heat, swelling, redness, and loss of function [1, 2, 3]. An inflammatory response is initiated by recognition of extracellular pathogen-associated molecular patterns (PAMPs), which are pathogenic components derived from invading pathogens through their molecular receptors called pattern recognition receptors (PRRs) expressed on the cell surfaces of macrophages [1, 3, 4]. One of the most intensively studied PRRs is Toll-like receptor 4 (TLR4), which is the molecular receptor for extracellular lipopolysaccharide (LPS), one of the most pathogenic components derived from the cell walls of Gram-negative bacteria [5]. Once extracellular LPS is recognized by TLR4 on macrophages, a macrophage-mediated inflammatory response is immediately induced. Inflammatory signaling pathways including nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IRFs) pathways are activated by inducing the signal transduction cascades of intracellular inflammatory signaling molecules. The activated inflammatory signaling pathways not only up-regulate expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and IL-6, and inflammatory genes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), but also increase the secretion of inflammatory mediators including nitric oxide (NO) and prostaglandin E2 (PGE2) [4, 6, 7, 8].

Recent studies have demonstrated that inflammatory responses are also strongly induced by intracellular inflammasomes, protein complexes that induce inflammatory responses in macrophages by activating gasdermin-D (GSDMD)-mediated pyroptosis and the secretion of pro-inflammatory cytokines including IL-1β and IL-18 in a caspase-1-dependent manner. Inflammasomes are classified in ‘canonical inflammsomes’, such as nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and absent in melanoma 2 (AIM2) inflammasomes as well as ‘non-canonical inflammasomes’, such as caspase-4, -5, and -11 [9, 10, 11, 12, 13]. These inflammsomes are activated by different types of ligands, leading to the induction of inflammatory responses [9, 10, 11, 12, 13].

Inflammation is a host defense mechanism to remove invading pathogens from the body. However, chronic inflammation is prolonged with repeated inflammatory responses. It can last for weeks to even years and is characterized by cycles of tissue injury and healing, consequently resulting in severe tissue damage. More critically, chronic inflammation has been posited as a major risk factor for the development of inflammatory/autoimmune diseases that are various arrays of disorders or conditions characterized by chronic inflammation against self-tissues [14, 15, 16, 17]. Rheumatic diseases are chronic inflammatory/autoimmune and degenerative diseases that mainly but not exclusively affect connective tissues, such as bones and cartilages in joints, tendons, ligaments, and muscles resulting in substantial morbidity and mortality. Since rheumatic diseases does not affect only connective tissues but some of them cause severe damages at other non-connective tissues and internal organs, there are more than 100 rheumatic diseases that are the biggest population in the inflammatory/autoimmune diseases with a large number of patients all over the world, and extensive studies have been focusing on these diseases. Many rheumatic diseases are caused by chronic inflammation and autoimmunity which are called ‘inflammatory/autoimmune rheumatic diseases’, and these diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Although the exact causes of rheumatic diseases are not fully understood, it is clear that chronic inflammatory responses are one of the major causative factors for development of rheumatic diseases. Therefore, it is reasonable that inflammasome-induced inflammatory responses in macrophages correlate with the development of inflammatory/autoimmune rheumatic diseases.

This review provides a general introduction to inflammasomes in macrophage-mediated inflammatory responses and discusses recent research on the role of inflammasomes in inflammatory/autoimmune rheumatic diseases. The aim of the review is to increase understanding of the inflammasome role in the pathogenesis of inflammatory/autoimmune rheumatic diseases. Insight on inflammasomes might contribute to the development of novel and promising anti-inflammatory drugs for the prevention and treatment of inflammatory/autoimmune rheumatic diseases.


Inflammatory responses are initially induced by PRRs in response to a variety of extracellular and intracellular PAMPs and stimuli. Several families of intracellular PRRs, such as NLRs, leucine-rich repeats (LRRs), AIM2, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and caspase-11 have been identified [9, 11, 13, 18, 19, 20, 21, 22, 23, 24, 25, 26]. Interestingly, some intracellular PRRs, such as NLRs and AIM2, induce a unique inflammatory response. These intracellular PRRs assemble protein complexes called ‘canonical inflammasomes’ consisting of a PRR, bipartite adaptor molecule, ASC, and pro-caspase-1. Different types of NLRs, such as NLRP1, NLRP3, and NLRC4, as well as the non-NLR family pathogen receptor AIM2 have been identified, and these pathogen receptors are activated by different stimuli [9, 11]. These canonical inflammasomes activate an inflammatory caspase, caspase-1, resulting in the maturation and secretion of pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis, an inflammatory form of programmed cell death that occurs with pathogen infection [9, 11, 25, 27, 28]. Recent studies have demonstrated that, caspase-11 directly recognizes intracellular LPS derived from Gram-negative bacteria and can activate inflammatory responses by inducing pyroptosis and secretion of IL-1β and IL-18 in macrophages [24]. This caspase-11-mediated inflammatory response is similar to NLRs- and AIM2-inflammasome-mediated inflammatory responses, but different from these canonical inflammasomes in composition and molecular mechanism during macrophage-mediated inflammatory responses. Therefore, this caspase-11 scaffold is considered a ‘non-canonical inflammasome’ [24, 25, 26, 29, 30, 31, 32, 33].

NLRP1 inflammasome is a protein complex consisting of NLRP1, which was identified as the first NLR family member to form inflammasomes [34]; ASC, which is an adaptor molecule; and pro-caspase-1 [9, 11]. NLRP1 is the only member of its family present in humans and has an amino-terminal pyrin domain (PYD), a nucleotide-binding and oligomerization domain (NACHT), leucine-rich repeats (LRRs), a functional-to-find domain (FIIND), and a carboxyl-terminal caspase recruit domain (CARD) (Fig. 1A). Unlike human NLRP1, several isoforms of mouse NLRP1, including NLRP1A, NLRP1B, and NLRP1C, have been identified. Interestingly, a PYD motif that exists in human NLRP1 is absent in the mouse NLRP1 family (Fig. 1A) [11]. Under the stimulation of Bacillus anthracis toxin, NLRP1 forms a NLRP1 inflammasome by direct interaction with procaspase-1 through their CARD motifs in macrophages (Fig. 1A) [35] and is subsequently activated to induce pyroptosis and caspase-1-mediated secretion of IL-1β and IL-18. The critical role of NLRP1 inflammasome in macrophage-mediated inflammatory responses is supported by studies reporting that pyroptosis and caspase-1-mediated secretion of IL-1β and IL-18 are abolished in macrophages isolated from Nlrp1 knock-out (KO) mice [35, 36].

Fig. 1
Structures and compositions of canonical (A-D) and non-canonical (E) inflammasomes.
(A) NLRP1 directly interacts with pro-caspase-1 through their CARD motifs. (B) NLPR3 interacts with pro-caspase-1 through a bipartite adaptor molecule, ASC. NLRP3 interacts with ASC through their PYD motifs, and ASC interacts with pro-caspase-1 through their CARD motifs. (C) NLRC4 directly interacts with pro-caspase-1 through their CARD motifs. (D) AIM2 interacts with pro-caspase-1 through a bipartite adaptor molecule, ASC. AIM2 interacts with ASC through their PYD motifs, and ASC interacts with pro-caspase-1 through their CARD motifs. (E) Pro-caspase-4/5 in a human and pro-caspase-11 in a mouse directly interact with the lipid A moiety of LPS through their CARD motifs. LRR, Leucine-rich repeat; NRL, nucleotide-binding oligomerization domain-like receptor; caspase, cysteine-aspartic protease; CARD, caspase recruit domain; NACHT, nucleotide binding and oligomerization domain; FIIND, function to find domain; AIM2, absent in melanoma 2; PYD, pyrin domain; HIN, hematopoietic interferon-inducible nuclear proteins; LPS, lipopolysaccharide. *Autocatalytic cleavage.
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NLRP3 consists of three major parts – an amino-terminal PYD motif, a NACHT motif, and carboxy-terminal LRRs (Fig. 1B). NLRP3 responds to a number of stimuli including uric acid, alum, silica, β-amyloids, nucleic acid hybrids, pore-generating toxins, extracellular adenosine triphosphates, hyaluronan, and various pathogens including bacteria, protozoans, viruses, and fungi [12, 37]. Under stimulation with these ligands, NLRP3 forms an inflammasome by binding with bipartite adaptor molecule ASC through its PYD motif and recruiting and binding with procaspase-1 through its CARD motif (Fig. 1B).

NLRC4 was initially discovered as an apoptotic-protease activating factor 1 (APAF1) due to structural similarity and is very similar to NLRP3 in structure but has a CARD motif at an amino-terminus instead of PYD (Fig. 1C). NLRC4 is also stimulated by bacterial ligands, such as bacterial flagellin and bacterial needle subunits [38, 39, 40, 41, 42]. In response to this stimulation, NLRC4 forms an inflammasome by directly binding with pro-caspase-1 through CARD motifs (Fig. 1C). Unlike NLRP3, NLRC4 does not need an adaptor molecule ASC to interact with pro-caspase-1.

AIM2 was identified as a direct sensor to detect intracellular double-stranded nucleic acids derived from invading pathogens and is different from NLRs due to the experimental observation that intracellular double-stranded nucleic acids from invading pathogens activate caspase-1, but not other inflammation effector molecules such as NLRs and TLRs [43]. Therefore, AIM2 was regarded as another type of intracellular receptor to trigger macrophage-mediated innate immune responses. As previously discussed, NLRP1, NLRP3, and NLRC4 are NLR family members, while AIM2 does not belong to this family, but is a p200 protein family member. AIM2 consists of two major parts – an amino-terminal PYD and a carboxy-terminal hematopoietic IFN-inducible nuclear protein (HIN) domain (Fig. 1D). In response to intracellular nucleic acids derived from pathogens, including Francisella tularensis, cytomegalovirus, and vaccinia virus, AIM2 assembles an AIM2 inflammasome by binding with bipartite adaptor molecule ASC through PYD motifs and recruiting procaspase-1 to bind with CARD motifs (Fig. 1D) [44, 45].

A non-canonical inflammasome was unexpectedly identified during the study of toxin-mediated inflammasome activation in macrophage-mediated inflammatory responses. Cholera toxin B (CTB) highly activated NLRP3 inflammasome and induced both pyroptosis and the secretion of IL-1β and IL-18. This inflammatory response was abolished in macrophages isolated from 129S6 mouse strain, which expresses a truncated and non-functional caspase-11 due to a polymorphism in the caspase-11 gene locus [24]. This observation strongly indicated that caspase-11, which is not a component of canonical inflammasomes, is a novel intracellular sensor that induces macrophage-mediated inflammatory responses and is different from the previously identified canonical inflammasomes and therefore named a ‘non-canonical inflammasome.’ Inactive pro-caspase-11 recognizes and directly binds with intracellular LPS, the most pathogenic component of Gram-negative bacteria, including E. coli, S. typhimurium, C. rodentium, L. pneumophilia, and Burkholderia spp., S. flexneri [29, 30, 31, 46, 47, 48, 49, 50, 51], and the binding between these two molecules is accomplished by direct interaction of the CARD motif of pro-caspase-11 with the lipid A moiety of LPS (Fig. 1E) [32]. Caspase-4 and caspase-5 are regarded as human homologues of mouse caspase-11. Similar to mouse caspase-11, their pro-forms pro-caspase-4 and pro-caspase-5 directly bind with the lipid A moiety of intracellular LPS through CARD motifs (Fig. 1E) [32, 52, 53]. Once these caspases-4/5/11 bind with intracellular LPS released from Gram-negative bacteria, caspase-4/5/11 non-canonical inflammasomes are activated by oligomerization of the caspase-4/5/11 monomers through their CARD motifs [25] and subsequently induce pyroptosis and the secretion of IL-1β and IL-18 by generating hollow-shaped pores composed of amino-terminal fragments of gasdermin D within macrophage membranes [25, 26, 33, 54, 55, 56, 57, 58]. Inflammasomes discussed here are summarized in Table 1.

Table 1
Types of inflammasomes
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Activation of inflammasomes is an essential step to induce inflammatory responses in macrophages, but chronic inflammatory response is a major risk factor for the development of inflammatory/autoimmune diseases. This indicates that uncontrolled and repeated activation of inflammasomes could play a critical role in the pathogenesis of inflammatory/autoimmune diseases. In this section, we discuss the role of inflammasomes in the inflammatory/autoimmune rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AP), and Sjögren's syndrome.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a serious lifelong autoimmune disease that primarily affects joints, is characterized by chronic synovial inflammation causing cartilage degradation and joint destruction, and has poor outcomes and limited treatment options [59, 60, 61, 62]. Since RA is the inflammatory/autoimmune disease with the highest prevalence worldwide, ranging from 0.5 to 1% of the population [63], the role of inflammasomes in RA has been actively investigated.

The relationship between inflammasomes and RA pathogenesis has been explored by genetic studies. Gene expression of NLRP3 inflammasome components was analyzed in RA patients receiving infliximab, an anti-TNF monoclonal antibody therapeutic. Gene expression of NLRP3 inflammasome components, including ASC, full-length NLRP3, short length NLRP3, and caspase-1, was significantly higher in RA patients compared to controls, and single-nucleotide polymorphisms (SNPs) at NLRP3 locus were associated with RA susceptibility and anti-TNF treatment [64, 65]. Genetic study in NLRP1 inflammasome relating to RA pathogenesis was also performed in a Chinese population. Sui et al. examined whether polymorphisms in the locus of NLRP1 gene are linked to susceptibility to RA and showed that NLRP1 gene polymorphism induces up-regulation of NLRP1 gene expression and is a risk factor for RA [66]. These studies clearly indicate that genetic variation by polymorphisms at the loci encoding inflammasomes is strongly associated with RA pathogenesis.

Caspase-1 is a crucial effector molecule in the inflammasome and induces pyroptosis and secretion of interleukin (IL)-1β, one of the critical pro-inflammatory cytokines associated with RA pathogenesis [9, 11]. The role of caspase-1 in RA was evaluated in a caspase-1–/– RA animal model, and the results showed that joint inflammation and cartilage degradation were dramatically reduced in caspase-1–/– mice induced with chronic arthritis [67], indicating that caspase-1 plays a critical role in RA pathogenesis.

Along with the genetic studies of inflammasomes in RA, the role of NLRP1 in RA pathogenesis has been established. Zhang et al. examined the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in RA pathogenesis and found that inhibition of 11β-HSD1 activity by its specific inhibitor, BVT-2733 significantly ameliorated the symptoms of arthritis including synovial inflammation and joint destruction by decreasing the serum level of IL-1β and suppressing the assembly of NLRP1 inflammasome in collagen-induced arthritic mice compared to controls [68]. Another study also demonstrated the role of NLRP1 in with RA pathogenesis. Li et al. investigated the role of P2X4, a purinergic receptor, in the development of RA in collagen-induced arthritic mice and showed that the inhibition of P2X4 mRNA expression by its antisense oligonucleotide effectively reduced the serum level of IL-1β and also suppressed the activation of NLRP1 inflammasome, leading to reduction of clinical scores in collagen-induced arthritis mice and human RA patients [69].

NLRP3 is another member of the NLR family, and Ippagunta et al. explored the role of NLRP3 inflammasome in RA. They evaluated RA pathogenesis in RA animal models that lack the components of NLRP3 inflammasome. ASC–/– mice were protected from arthritis induction, whereas NLRP3–/– and caspase-1–/– mice were susceptible to arthritis induction [70]. This result was different from the result by Joosten et al. [67], possibly due to the different RA animal models used. Joosten et al. induced arthritis in mice by transferring the serum of K/BxN mice containing the antibodies to recognize glucose-6-phosphate isomerase [71], whereas Ippagunta et al. induced arthritis in mice by injecting collagen (collagen-induced arthritis), suggesting that arthritis induction by different methods might activate different types of immune cells and molecules, possibly resulting in different experimental results. The regulation of NLRP3 inflammasome in RA pathogenesis was investigated. Vande Walle et al. demonstrated that lack of A20, a rheumatoid arthritis susceptibility gene, increased the expression of NLRP3 and pro-IL-1β genes, resulting in induction of NLRP3 inflammasome-mediated caspase-1 activation, pyroptosis, and IL-1β secretion [72]. Moreover, deficiency of NLRP3 significantly suppressed the progression of arthritis and cartilage degradation in A20–/– mice [72], indicating that negative regulation of the NLRP3 inflammasome expression attenuates the pathogenesis of RA. Ruscitti et al. also evaluated the production of IL-1β and activation of NLRP3 inflammasome in the monocytes of RA patients and showed that a significant increase of IL-1β production in the monocytes obtained from RA patients was mediated by the activation of NLRP3 inflammasome [73].

The activation of NLRP3 inflammasome in RA patients was further investigated. Choulaki et al. demonstrated the production of NLRP3 inflammasome components in RA patients and showed that active RA patients had not only higher intracellular levels of NLRP3 inflammasome components including NLRP3, ASC, active caspase-1, and pro-IL-1β, but also increased secretion of IL-1β [74]. Li et al. also examined the activity of NLRP3 inflammasome in arthritic rats. In accordance with previous studies, the activation of NLRP3 inflammasome and the secretion of IL-1β were induced in the synovium of arthritic rats [75]. Inhibition of NLRP3 activity by a clematichinenoside AR, a triterpene saponin extracted from the medicinal plant Clematis manshurica Rupr, suppressed joint inflammation in arthritic rats [75]. Interestingly, a recent study explored the role of NLRP3 in RA pathogenesis using mesenchymal stem cells. Shin et al. administered human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into collagen-induced arthritis mice and evaluated their therapeutic effect and underlying mechanisms. Systemic administration of hUCB-MSCs dramatically ameliorated the symptoms of arthritis in collagen-induced arthritis mice by suppressing activation of NLRP3 inflammasome in macrophages [76].

Taken together, these results, as described in Fig. 2A strongly indicate that inflammasome activation is a risk factor for the pathogenesis of RA, and selective inhibition of inflammasomes effectively ameliorates RA symptoms and retards RA progression.

Fig. 2
Graphical summary of the roles of inflammasomes in inflammatory/autoimmune rheumatic diseases.
(A) The SNPs and gene expression of NLRP1 and NLRP3, and intracellular NLRP3 level are increased in RA compared to healthy normal control. The activation of NLRP1 and NLRP3 inflammasomes by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. In contrast, in a certain condition, NLRP3 knock-out induces RA. A dash line indicates knock-out of NLRP3 gene. (B) The SNPs of NLRP1 and the gene expression of NLRP3 are increased in SLE compared to healthy normal control. The activation of NLRP3 inflammasome by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. Intracellular AIM2 level is increased in SLE compared to healthy normal control. In contrast, in a certain condition, intracellular levels of NLRP1, NLRP3, and AIM2 are decreased in SLE compared to healthy normal control. Dash lines indicate the decrease in the intracellular levels of NLRP1, NLRP3, and AIM2. (C) The SNPs of CARD, a critical domain of NLRs are increased in AS compared to healthy normal control. Intracellular levels of IL-1 and caspase-1that are down-stream effector molecules of inflammasomes are increased in AS compared to healthy normal control. (D) The gene expression of NLRP3 and intracellular NLRP3 level are increased in SS compared to healthy normal control. The activation of NLRP3 inflammasome by the assembly with ASC and pro-caspase-1 is induced in RA compared to healthy normal control. SNPs, single nucleotide polymorphisms; NRL, nucleotide-binding oligomerization domain-like receptor; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; AS, ankylosing spondylitis; SS, Sjögren's syndrome.
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Systemic lupus erythematosus

Systemic lupus erythematosus (SLE), also known as lupus, is a rare inflammatory/autoimmune rheumatic disease that attacks normal healthy tissues in many parts of the body and has a complex pathogenesis. SLE is characterized by various symptoms including inflammatory joints, nephritis, mouth ulcer, swollen lymph nodes, and butterfly-shaped red rash on the face, which is the most typical symptom of SLE [77]. The incidence and prevalence of SLE vary worldwide but is steadily increasing [77]. Although SLE is a rare inflammatory/autoimmune disease, it affects almost all parts of the body, and the symptoms are severe and life threatening. Therefore, many studies have focused on exploring not only the molecular mechanisms of SLE pathogenesis, but also the development of effective therapeutic strategies for SLE.

Active involvement of inflammasomes in SLE pathogenesis has been frequently hypothesized and demonstrated by many research groups. Pontillo et al. examined gene mutations and polymorphisms of inflammasomes and inflammasome effector molecules by SNP analysis in SLE patients and found several SNPs in NLRP1 to be significantly associated with SLE pathogenesis [78].

The role of NLRP3 inflammasome in SLE pathogenesis has been actively explored by many research groups. Shin et al. reported that U1-small nuclear ribonucleoprotein (U1-snRNP), a self nuclear molecule, activated the NLRP3 inflammasome in human monocytes depending on anti-U1-snRNP autoantibodies, which are characteristically found in inflammatory/autoimmune diseases including SLE [79], leading to IL-1β production [80]. This result indicates that self molecules and their autoantibodies can induce inflammatory responses and SLE pathogenesis by activating inflammasomes, such as NLRP3. Neutrophil extracellular traps (NETs) are networks of extracellular fibers primarily consisting of anti-microbial peptides and critical enzymes for host defense [81] and have been suggested to participate in the development of SLE [82, 83]. Kahlenberg et al. isolated NETs from human SLE patients and demonstrated that NET-mediated activation of NLRP3 inflammasome was significantly enhanced in macrophages derived from SLE patients. Moreover, NETs activated caspase-1, a downstream effector molecule of NLRP3 inflammasome, resulting in secretion of IL-1β and IL-18 in macrophages [84]. These results indicate that increased activation of NLRP3 inflammasome plays a critical role in NET-mediated pathogenesis of SLE.

A pathogenic hallmark of SLE is the autoinflammatory responses against self nuclear antigens, such as circulating double-stranded DNAs (dsDNAs) and anti-dsDNA antibodies, which are found in the sera of SLE patients [85, 86]. Shin et al. demonstrated that dsDNA and anti-dsDNA autoantibodies induced IL-1β production by activating NLRP3 inflammasome and caspase-1 in human monocytes, leading to production of IL-17 from the IL-1R1+ memory CD4+ T-cells [87]. This plays a crucial role in the pathogenesis of SLE by facilitating production of anti-dsDNA antibodies from B-cells and inducing Th17 cell responses in SLE patients [88, 89]. The complement component C1q is a risk factor for the development of SLE with its deficiency [90] and was demonstrated to suppress the expression of NLRP3 in human macrophages [91]. Interestingly, the activity of NLRP3 inflammasome was inhibited during C1q-mediated phagocytosis of apoptotic lymphocytes [91], suggesting that activation of NLRP3 inflammasome by C1q absence might contribute to development of SLE. Another study provided direct evidence for the role of NLRP3 inflammasome in the pathogenesis of SLE. Lu et al. examined the role of NLRP3 inflammasome in SLE development using a pristine-induced lupus mouse model and reported that NLRP3 inflammasome was hyperactivated and lupus-like symptoms were more severely developed with higher mortality in the Nlrp3R258W mice that carry a gain-of-function mutation compared to wild type lupus mice [92]. Moreover, a mechanistic study clearly demonstrated that elevated serum levels of anti-dsDNA autoantibodies activated NLRP3 inflammasome and caspase-1 and induced IL-1β secretion in lupus mice [93].

On the other hand, a negative correlation of NLRP3 inflammasome with SLE disease activity was also reported. Yang et al. demonstrated that expression of NLRP3 and NLRP1 inflammasomes was significantly down-regulated in peripheral blood mononuclear cells (PBMCs) derived from patients with SLE compared to those from healthy controls and negatively correlated with SLE disease severity [94]. Lech et al. investigated the role of NLRP3 inflammasome in SLE using mice models lacking the genes of NLRP3 inflammasome components and reported a lack of NLRP3- and ASC-induced lupus-like symptoms in mice [95]. That finding offers further direct evidence that NLRP3 inflammasome plays a pivotal role in the development and progression of SLE. Sester et al. also reported that NLRP3 was absent due to a NLRP3 point mutation, and NLRP3 inflammasome-mediated responses were completely absent in the NZB lupus mice [96].

These results strongly indicate that NLRP3 inflammasome is a risk factor for the development and progression of SLE, while NLRP3 inflammasome negatively correlates with SLE pathogenesis under some conditions.

AIM2 is one of the p200 protein family members to recognize intracellular double-stranded nucleic acids. By recognizing intracellular nucleic acids, AIM2 inflammasome is assembled and activated, leading to activation of caspase-1 and subsequent induction of pyroptosis and IL-1β secretion in macrophages [9, 11]. Formation of AIM2 an inflammasome in response to intracellular double-stranded nucleic acids suggests that an AIM2 inflammasome might be activated in inflammatory/autoimmune diseases, including SLE. Indeed, the serum levels of IL-1β and type I interferons (IFNs) were significantly higher in active SLE patients compared to the normal healthy control [97, 98]. Zhang et al. further demonstrated that the expression of AIM2 was correlated with severity of disease in SLE patients and a lupus mouse model [99]. Moreover, inhibition of AIM2 expression significantly ameliorated SLE symptoms by suppressing macrophage activation and inflammatory responses in a lupus mouse model [99]. Ding et al. confirmed that mRNA expression level of AIM2 was much higher in spleen, liver, and peripheral blood mononuclear cells of SLE patients than in healthy control individuals [100].

Some other studies, however, have reported that AIM2 inhibition might induce the pathogenesis of SLE. p202 is another member of the p200 protein family and has been reported to be up-regulated in many lupus-prone mouse strains [101, 102]. p202 has been demonstrated to inhibit AIM2-mediated activation of caspase-1 and to be associated with lupus susceptibility [103, 104, 105, 106]. AIM2 expression in non-lupus prone splenic cells, lupusprone splenic cells, and macrophages expressing high level of p202 was proven to be inversely correlated with p202 expression [107]. In addition, Sester et al. reported that AIM2 inflammasome responses were suppressed due to the high expression of AIM2 antagonist p202 in NZB lupus mice, resulting in low production of IL-1β [96]. These results indicate that AIM2 might be a double-edged sword for SLE pathogenesis.

Lupus nephritis (LN), one of the most serious complications of SLE, is inflammation of the kidneys caused by SLE and the major cause of morbidity and mortality of SLE patients. Many studies have demonstrated the role of inflammasomes in LN during SLE pathogenesis. Gene expression of inflammasome components in LN has been examined. Kahlenberg et al. reported that gene expression of NLRP3 and caspase-1 was significantly up-regulated in LN biopsies [108]. The roles of inflammasomes and their downstream effector molecules, including caspase-1, IL-1β, and IL-18, were also actively explored in LN using various inhibitors and pharmacological compounds. Tsai et al. reported that epigallocatechin-3-gallate, the major bioactive polyphenol, ameliorated symptoms of LN by inhibiting mRNA/protein expression of NLRP3 and the production of caspase-1, IL-1β, and IL-18, which are inflammasome effector molecules in a lupus-prone mice model [109]. Zhao et al. demonstrated that Bay11-7082, a selective inhibitor of the NLRP3 inflammasome, notably decreased serum levels of anti-dsDNA autoantibodies and pro-inflammatory cytokines including IL-1β and TNF-α and ameliorated the symptoms of LN in a lupus mouse model [110]. Zhao et al. also reported that thiadiazolidinone 8 (TDZD-8), a selective inhibitor of glycogen synthase kinase 3β (GSK-3β), inhibited the activation of NLRP3 inflammasome by suppressing caspase-1 activation and IL-1β production in lupus mouse models [111]. Ka et al. further explored the role of NLRP3 inflammasome in LN and reported that citral, a main active ingredient in the herbal medicine Litsea cubeca , significantly inhibited activation of NLRP3 inflammasome and caspase-1 and the secretion of IL-1β. Moreover, it effectively ameliorated LN symptoms in accelerated and severe LN mice [112]. In addition, Li et al. demonstrated that A20, a TNF-induced protein 3 (TNFAIP3) known as a negative modulator of inflammation, markedly suppressed the activation of NLRP3 inflammasome and mitigated LN symptoms in pristine-induced lupus mice [113], and Yuan et al. reported that isoflurane abrogated the formation and activation of renal NLRP3 inflammasome and ameliorated renal dysfunction and injury in MRL/lpr lupus mice [114]. P2X7 receptor (P2X7R), a member of the P2X receptor family, is an ATP-gated ionotropic channel protein mainly expressed on innate immune cells, such as macrophages and dendritic cells [115, 116]. It has been reported that P2X7R induces the activation of a NLRP3 inflammasome and the secretion of IL-1β by directly interacting with NLRP3 inflammasome scaffold protein in response to extracellular stimulus such as ATP [117, 118]. Interestingly, Bours et al. explored the role of the P2X7R-inflammasome axis in SLE using lupus mouse models and demonstrated that inhibition of P2X7R showed the beneficial effects in LN in lupus mouse models [119]. Zhao et al. further demonstrated that gene expression of P2X7R-NLRP3 inflammasome signaling molecules, including NLRP3, ASC, and caspase-1, was significantly up-regulated in the kidneys of lupus mice compared to healthy control mice [120]. Moreover, inhibition of P2X7R by its selective inhibitor, brilliant blue G (BBG), suppressed the assembly and activation of the NLRP3 inflammasome and secretion of IL-1β, leading to a significant reduction in nephritis symptoms in lupus mice [120]. In addition to inflammasomes, the role of caspase-1 was also explored in LN. Kahlenberg et al. reported that caspase-1–/– mice were more resistant to lupus and kidney inflammation [121]. The roles of inflammasomes in the pathogenesis of SLE were described in Fig. 2B.

Ankylosing spondylitis and spondyloarthritis

Spondyloarthritis (SpA) and ankylosing spondylitis (AS), the prototype disease of SpA, are types of inflammatory/autoimmune arthritis that primarily affect the axial vertebrae. These diseases cause vertebral fusion which makes the spine less flexible, resulting in a hunched-forward posture and is mainly characterized by severe, chronic pain and discomfort, with significant morbidity and mortality risk [122, 123]. In spite of the evidence that environmental factors, including gut dysbiosis contribute to developing AS [124], increasing numbers of studies have reported that the disease risk is largely influenced by a genetic factors, and more than 60 genes are associated with the risk of AS [125, 126, 127]. Although large-scale studies of the prevalence and incidence of AS are few, the prevalence of AS is generally thought to range from 0.1 to 1.4% worldwide and affects men more often than women [128]. Many studies have examined epidemiological trends in AS. However, these studies have yielded discrepant results due to study design, age, geographic location, genetic susceptibility, disease ascertainment, and ethnicity of patients [128, 129, 130, 131]. In addition, some AS incidence rate reporting has focused only on Europe [131, 132, 133, 134, 135].

As described earlier, activation of inflammasomes results in the production of the IL-1β from macrophages. Interestingly, the production of IL-1 has been found to be highly induced in AS [136], suggesting the possibility that inflammasomes might be activated and IL-1β production induced in AS. The clinical efficacy of anti-IL-1 monoclonal antibody therapeutics have been examined in AS patients. Tan et al. treated AS patients with Anakinra, an anti-IL-1 monoclonal antibody drug, and reported that Anakinra effectively ameliorated AS symptoms in 67% of the patients [136]. Although this study showed the possibility that inflammasomes could be involved in AS pathogenesis through IL-1β production, it did not provide a direct evidence.

Few studies have reported on the roles of inflammasomes in AS. Therefore, studies to examine the direct role of inflammasomes in AS are needed. Genetic study has established the association between inflammasomes and AS. Kastbom et al. evaluated SNPs in CARD, which is the critical domain of an inflammasome, in 492 AS patients from southern Sweden and reported that a SNP in the CARD8 minor allele was associated with reduced risk of AS [137]. This suggests the possibility that normal inflammasomes containing CARDs might be risk factors for AS pathogenesis.

Activation of caspase-1 is the hallmark of inflammasome activation. Son et al. determined the level of caspase-1 in patients with several types of arthritic diseases including gout, inflammatory arthritis, osteoarthritis, and SpA and reported that caspase-1 level was significantly higher in SpA than in other arthritic diseases [138]. Therefore, caspase-1 could be a biomarker of SpA and helpful in differentiating it from other types of arthritic diseases.

In spite of some studies describing the roles of inflammasomes in AS and SpA (Fig. 2C), studies to provide more direct evidence of the association of inflammasomes in these diseases are needed.

Sjögren's syndrome

Sjögren's syndrome (SS) is a debilitating long-term chronic inflammatory/autoimmune disease in which moisture-generating exocrine gland tissues, such as the tear and salivary glands are primarily targeted by the immune system and is characterized by the development of dry mouth and dry eyes [59, 139]. The hallmarks of SS are sicca symptoms, but various organ manifestations could also occur [140]. There are two types of SS – primary SS (pSS), which is characterized by loss of salivary and lacrimal fluid, resulting in severe disease manifestations [141], and secondary SS (sSS), which is diagnosed by pSS diagnosis as well as other inflammatory/autoimmune diseases, including RA, SLE, systemic sclerosis, multiple sclerosis, and autoimmune hepatitis and thyroiditis [59, 142]. The overall prevalence of both pSS and sSS which is more common than pSS is at least 0.4% worldwide with the higher prevalence in Europe [143, 144], and SS develops more frequently in women than men ranging between 9:1 to 19:1depending on the regions [140].

Although SS is a rare autoimmune/inflammatory disease, many studies have reported the role of inflammasomes in the pathogenesis of SS. The expression level and activity of caspase-1 were examined in SS mouse models, and the results clearly showed that expression and activity of caspase-1 were induced in SS salivary tissues at an early disease state [145, 146]. This result was confirmed in human SS patients. The expression of inflammasome-related genes, such as P2X7, NLRP3, and caspase-1, was significantly up-regulated in human pSS salivary tissue and correlated with anti-Ro autoantibody presence and focal lymphocytic sialadenitis [147], and the expression of NLRP3 and IL-1β was significantly induced in patients with SS dry eye [148]. The production of both IL-1 and IL-18 resulting from inflammasome activation was highly induced in human SS patients as well as SS mouse models [145, 147, 149, 150, 151, 152, 153]. These studies indicate that the inflammasome is actively involved in the onset and development of SS.

As discussed earlier, P2X7R directly interacts with and activates the NLRP3 inflammasome, resulting in induction of IL-1β secretion, and the role of the inflammasome in the P2X7R-inflammasome axis was also explored in SS using an animal model. P2X7R-deficient mice were protected from inflammation of a salivary gland, and activation of P2X7R by local delivery of P2X7R agonist in mice induced severe inflammation in a salivary gland [154], indicating that the activation of P2X7R could induce SS-like symptoms in mouse models by activating NLRP3 inflammasome. Another study reported the role of the P2X7R-inflammasome axis in human SS patients. They showed that expression of the genes in the P2X7R-inflammasome axis, including P2X7R, NLRP3, caspase-1, and IL-18, was significantly induced in the salivary gland specimens of SS patients [147].

Taken together, these studies, as described in Fig. 2D strongly suggest that the activation of inflammasome, especially NLRP3 inflammasome, in salivary gland tissue might be a critical event for the pathogenesis and progress of SS.


Inflammation is an innate immune response mediated mainly by macrophages in order to protect the body from pathogen invasion. One hallmark of macrophage-mediated inflammatory responses is activation of inflammasomes. Inflammasomes are intracellular protein complexes that can activate caspase-1, resulting in the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18 and induction of pyroptosis. They include NLR family inflammasomes, including NLRP1, NLRP3, and NLRC4 as well as non-NLR family inflammasomes, such as AIM2. Although activation of inflammasomes during the inflammatory response is a host defense mechanism, these inflammasomes play critical roles in chronic inflammatory responses that are regarded as the major cause of inflammatory/autoimmune rheumatic diseases. Several studies have demonstrated that inflammasomes and downstream effector molecules including caspase-1, IL-1β, and IL-18 are highly expressed and activated in inflammatory/autoimmune rheumatic diseases, and that the activation of inflammasomes is a risk factor for the development and progression of these diseases. On the other hand, several studies have also claimed that some types of inflammasomes, such as NLRP3 and AIM2, negatively correlate with the pathogenesis of these diseases under certain conditions. The roles of inflammasomes in each inflammatory/autoimmune disease are summarized in Table 2.

Table 2
Roles of inflammasomes in inflammatory/autoimmune diseases
Click for larger image

In spite of a number of successful studies reporting the roles of inflammsomes in the inflammatory/autoimmune rheumatic diseases, no study demonstrating the roles of non-canonical inflammasomes in these diseases has been reported. In addition, no study investigating the functional crosstalk between canonical and non-canonical inflammasomes as well as between different types of canonical inflammasomes during the pathogenesis of these diseases has been reported. Therefore, these studies need to be further investigated to explain how they cooperate and make synergistic or antagonistic effects during the pathogenesis of these diseases. Moreover, extensive studies on the useful strategies to selectively target and regulate the activation of inflammasomes and their pathways during inflammatory responses, such as inflammasome-specific small interfering RNAs, a recently developed inflammasome-targeting intracellular antibody technology [155], and the agents to inhibit the inflammasome assembly are highly required for developing effective drugs that could be used for these diseases. Given strong evidence of the critical role of inflammasomes in macrophage-mediated inflammatory responses and in inflammatory/autoimmune rheumatic diseases, targeting inflammasomes represents a novel and promising strategy for the prevention and treatment of inflammatory/autoimmune rheumatic diseases.


Author contributions:Y.S.Y. designed and wrote the manuscript.

CONFLICTS OF INTEREST:The author declare no conflicts of interest.

1. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197–216.
2. Yi YS. Folate receptor-targeted diagnostics and therapeutics for inflammatory diseases. Immune Netw 2016;16:337–343.
3. Kayama H, Nishimura J, Takeda K. Regulation of intestinal homeostasis by innate immune cells. Immune Netw 2013;13:227–234.
4. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805–820.
5. Song DH, Lee JO. Sensing of microbial molecular patterns by Tolllike receptors. Immunol Rev 2012;250:216–229.
6. Yi YS, Son YJ, Ryou C, Sung GH, Kim JH, Cho JY. Functional roles of Syk in macrophage-mediated inflammatory responses. Mediators Inflamm 2014;2014:270302
7. Yu T, Yi YS, Yang Y, Oh J, Jeong D, Cho JY. The pivotal role of TBK1 in inflammatory responses mediated by macrophages. Mediators Inflamm 2012;2012:979105
8. Byeon SE, Yi YS, Oh J, Yoo BC, Hong S, Cho JY. The role of Src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm 2012;2012:512926
9. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell 2014;157:1013–1022.
10. Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61–75.
11. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016;16:407–420.
12. Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 2012;28:137–161.
13. Yi YS. Caspase-11 non-canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage-mediated inflammatory responses. Immunology 2017;152:207–217.
14. Kaur M, Singh M, Silakari O. Inhibitors of switch kinase ‘spleen tyrosine kinase’ in inflammation and immune-mediated disorders: a review. Eur J Med Chem 2013;67:434–446.
15. Park MH, Igarashi K. Polyamines and their metabolites as diagnostic markers of human diseases. Biomol Ther (Seoul) 2013;21:1–9.
16. Ham M, Moon A. Inflammatory and microenvironmental factors involved in breast cancer progression. Arch Pharm Res 2013;36:1419–1431.
17. Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP. Diabetes mellitus and inflammation. Curr Diab Rep 2013;13:435–444.
18. Chen G, Shaw MH, Kim YG, Nuñez G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol 2009;4:365–398.
19. Kang TJ, Chae GT. The role of intracellular receptor NODs for cytokine production by macrophages infected with mycobacterium leprae. Immune Netw 2011;11:424–427.
20. Tartey S, Takeuchi O. Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells. Int Rev Immunol 2017;36:57–73.
21. Motta V, Soares F, Sun T, Philpott DJ. NOD-like receptors: versatile cytosolic sentinels. Physiol Rev 2015;95:149–178.
22. Kedzierski Ł, Montgomery J, Curtis J, Handman E. Leucine-rich repeats in host-pathogen interactions. Arch Immunol Ther Exp (Warsz) 2004;52:104–112.
23. Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: role in DNA sensing, inflammation, and innate immunity. Eur J Immunol 2016;46:269–280.
24. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM. Non-canonical inflammasome activation targets caspase-11. Nature 2011;479:117–121.
25. Yang J, Zhao Y, Shao F. Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity. Curr Opin Immunol 2015;32:78–83.
26. Diamond CE, Khameneh HJ, Brough D, Mortellaro A. Novel perspectives on non-canonical inflammasome activation. Immunotargets Ther 2015;4:131–141.
27. Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–832.
28. Lee MS. Role of innate immunity in diabetes and metabolism: recent progress in the study of inflammasomes. Immune Netw 2011;11:95–99.
29. Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012;490:288–291.
30. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 2013;341:1250–1253.
31. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszyński A, Forsberg LS, Carlson RW, Dixit VM. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 2013;341:1246–1249.
32. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187–192.
33. Stowe I, Lee B, Kayagaki N. Caspase-11: arming the guards against bacterial infection. Immunol Rev 2015;265:75–84.
34. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 2002;10:417–426.
35. Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006;38:240–244.
36. Kovarova M, Hesker PR, Jania L, Nguyen M, Snouwaert JN, Xiang Z, Lommatzsch SE, Huang MT, Ting JP, Koller BH. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol 2012;189:2006–2016.
37. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397–411.
38. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213–218.
39. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat Immunol 2006;7:569–575.
40. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozören N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nùñez G. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nat Immunol 2006;7:576–582.
41. Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, Leaf IA, Aderem A. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A 2010;107:3076–3080.
42. Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011;477:596–600.
43. Muruve DA, Pétrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, Parks RJ, Tschopp J. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 2008;452:103–107.
44. Alnemri ES. Sensing cytoplasmic danger signals by the inflammasome. J Clin Immunol 2010;30:512–519.
45. Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol 2010;10:688–698.
46. Akhter A, Caution K, Abu Khweek A, Tazi M, Abdulrahman BA, Abdelaziz DH, Voss OH, Doseff AI, Hassan H, Azad AK, Schlesinger LS, Wewers MD, Gavrilin MA, Amer AO. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity 2012;37:35–47.
47. Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, Fitzgerald KA. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 2012;150:606–619.
48. Aachoui Y, Leaf IA, Hagar JA, Fontana MF, Campos CG, Zak DE, Tan MH, Cotter PA, Vance RE, Aderem A, Miao EA. Caspase-11 protects against bacteria that escape the vacuole. Science 2013;339:975–978.
49. Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A 2013;110:1851–1856.
50. Casson CN, Copenhaver AM, Zwack EE, Nguyen HT, Strowig T, Javdan B, Bradley WP, Fung TC, Flavell RA, Brodsky IE, Shin S. Caspase-11 activation in response to bacterial secretion systems that access the host cytosol. PLoS Pathog 2013;9:e1003400
51. Gurung P, Malireddi RK, Anand PK, Demon D, Vande Walle L, Liu Z, Vogel P, Lamkanfi M, Kanneganti TD. Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens. J Biol Chem 2012;287:34474–34483.
52. Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 2015;6:8761
53. Casson CN, Yu J, Reyes VM, Taschuk FO, Yadav A, Copenhaver AM, Nguyen HT, Collman RG, Shin S. Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens. Proc Natl Acad Sci U S A 2015;112:6688–6693.
54. Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 2017;42:245–254.
55. Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci U S A 2016;113:7858–7863.
56. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 2015;25:1285–1298.
57. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015;526:660–665.
58. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015;526:666–671.
59. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:15–25.
60. Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108–1111.
61. Pincus T, Brooks RH, Callahan LF. Prediction of long-term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures. Ann Intern Med 1994;120:26–34.
62. Yi YS, Ayala-López W, Kularatne SA, Low PS. Folate-targeted hapten immunotherapy of adjuvant-induced arthritis: comparison of hapten potencies. Mol Pharm 2009;6:1228–1236.
63. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010;376:1094–1108.
64. Mathews RJ, Robinson JI, Battellino M, Wong C, Taylor JC, Eyre S, Churchman SM, Wilson AG, Isaacs JD, Hyrich K, Barton A, Plant D, Savic S, Cook GP, Sarzi-Puttini P, Emery P, Barrett JH, Morgan AW, McDermott MF. Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis 2014;73:1202–1210.
65. Jenko B, Praprotnik S, Tomšic M, Dolžan V. NLRP3 and CARD8 polymorphisms influence higher disease activity in rheumatoid arthritis. J Med Biochem 2016;35:319–323.
66. Sui J, Li H, Fang Y, Liu Y, Li M, Zhong B, Yang F, Zou Q, Wu Y. NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum 2012;64:647–654.
67. Joosten LA, Netea MG, Fantuzzi G, Koenders MI, Helsen MM, Sparrer H, Pham CT, van der Meer JW, Dinarello CA, van den Berg WB. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1β. Arthritis Rheum 2009;60:3651–3662.
68. Zhang L, Dong Y, Zou F, Wu M, Fan C, Ding Y. 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. Int Immunopharmacol 2013;17:489–494.
69. Li F, Guo N, Ma Y, Ning B, Wang Y, Kou L. Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis. Inflammation 2014;37:146–153.
70. Ippagunta SK, Brand DD, Luo J, Boyd KL, Calabrese C, Stienstra R, Van de Veerdonk FL, Netea MG, Joosten LA, Lamkanfi M, Kanneganti TD. Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis. J Biol Chem 2010;285:12454–12462.
71. Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C, Gravallese E, Mathis D, Benoist C. Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med 2002;196:77–85.
72. Walle LV, Van Opdenbosch N, Jacques P, Fossoul A, Verheugen E, Vogel P, Beyaert R, Elewaut D, Kanneganti TD, van Loo G, Lamkanfi M. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 2014;512:69–73.
73. Ruscitti P, Cipriani P, Di Benedetto P, Liakouli V, Berardicurti O, Carubbi F, Ciccia F, Alvaro S, Triolo G, Giacomelli R. Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol 2015;182:35–44.
74. Choulaki C, Papadaki G, Repa A, Kampouraki E, Kambas K, Ritis K, Bertsias G, Boumpas DT, Sidiropoulos P. Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther 2015;17:257.
75. Li Y, Zheng JY, Liu JQ, Yang J, Liu Y, Wang C, Ma XN, Liu BL, Xin GZ, Liu LF. Succinate/NLRP3 inflammasome induces synovial fibroblast activation: therapeutical effects of clematichinenoside AR on arthritis. Front Immunol 2016;7:532.
76. Shin TH, Kim HS, Kang TW, Lee BC, Lee HY, Kim YJ, Shin JH, Seo Y, Choi SW, Lee S, Shin K, Seo KW, Kang KS. Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis. Cell Death Dis 2016;7:e2524
77. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet 2014;384:1878–1888.
78. Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S, Sandrin-Garcia P. Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity 2012;45:271–278.
79. Kattah NH, Kattah MG, Utz PJ. The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev 2010;233:126–145.
80. Shin MS, Kang Y, Lee N, Kim SH, Kang KS, Lazova R, Kang I. U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes. J Immunol 2012;188:4769–4775.
81. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007;5:577–582.
82. Knight JS, Kaplan MJ. Lupus neutrophils: ‘NET’ gain in understanding lupus pathogenesis. Curr Opin Rheumatol 2012;24:441–450.
83. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, Bassett R, Amuro H, Fukuhara S, Ito T, Liu YJ, Gilliet M. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011;3:73ra19
84. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol 2013;190:1217–1226.
85. Sano H, Takai O, Harata N, Yoshinaga K, Kodama-Kamada I, Sasaki T. Binding properties of human anti-DNA antibodies to cloned human DNA fragments. Scand J Immunol 1989;30:51–63.
86. Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 2005;115:407–417.
87. Shin MS, Kang Y, Lee N, Wahl ER, Kim SH, Kang KS, Lazova R, Kang I. Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. J Immunol 2013;190:1407–1415.
88. Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang YT, Tsokos GC. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol 2008;181:8761–8766.
89. Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 2010;12:R53
90. Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 2004;22:431–456.
91. Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol 2012;188:5682–5693.
92. Lu A, Li H, Niu J, Wu S, Xue G, Yao X, Guo Q, Wan N, Abliz P, Yang G, An L, Meng G. Hyperactivation of the NLRP3 inflammasome in myeloid cells leads to severe organ damage in experimental lupus. J Immunol 2017;198:1119–1129.
93. Zhang H, Fu R, Guo C, Huang Y, Wang H, Wang S, Zhao J, Yang N. Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages. J Transl Med 2016;14:156.
94. Yang Q, Yu C, Yang Z, Wei Q, Mu K, Zhang Y, Zhao W, Wang X, Huai W, Han L. Deregulated NLRP3 and NLRP1 inflammasomes and their correlations with disease activity in systemic lupus erythematosus. J Rheumatol 2014;41:444–452.
95. Lech M, Lorenz G, Kulkarni OP, Grosser MO, Stigrot N, Darisipudi MN, Günthner R, Wintergerst MW, Anz D, Susanti HE, Anders HJ. NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. Ann Rheum Dis 2015;74:2224–2235.
96. Sester DP, Sagulenko V, Thygesen SJ, Cridland JA, Loi YS, Cridland SO, Masters SL, Genske U, Hornung V, Andoniou CE, Sweet MJ, Degli-Esposti MA, Schroder K, Stacey KJ. Deficient NLRP3 and AIM2 inflammasome function in autoimmune NZB mice. J Immunol 2015;195:1233–1241.
97. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 2006;6:823–835.
98. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 2007;13:543–551.
99. Zhang W, Cai Y, Xu W, Yin Z, Gao X, Xiong S. AIM2 facilitates the apoptotic DNA-induced systemic lupus erythematosus via arbitrating macrophage functional maturation. J Clin Immunol 2013;33:925–937.
100. Ding L, Dong G, Zhang D, Ni Y, Hou Y. The regional function of cGAS/STING signal in multiple organs: One of culprit behind systemic lupus erythematosus? Med Hypotheses 2015;85:846–849.
101. Panchanathan R, Xin H, Choubey D. Disruption of mutually negative regulatory feedback loop between interferon-inducible p202 protein and the E2F family of transcription factors in lupus-prone mice. J Immunol 2008;180:5927–5934.
102. Haywood ME, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ, Morley BJ. Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun 2006;7:250–263.
103. Choubey D, Panchanathan R. Interferon-inducible Ifi200-family genes in systemic lupus erythematosus. Immunol Lett 2008;119:32–41.
104. Choubey D, Duan X, Dickerson E, Ponomareva L, Panchanathan R, Shen H, Srivastava R. Interferon-inducible p200-family proteins as novel sensors of cytoplasmic DNA: role in inflammation and autoimmunity. J Interferon Cytokine Res 2010;30:371–380.
105. Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL, Hume DA, Stacey KJ. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 2009;323:1057–1060.
106. Yin Q, Sester DP, Tian Y, Hsiao YS, Lu A, Cridland JA, Sagulenko V, Thygesen SJ, Choubey D, Hornung V, Walz T, Stacey KJ, Wu H. Molecular mechanism for p202-mediated specific inhibition of AIM2 inflammasome activation. Cell Rep 2013;4:327–339.
107. Panchanathan R, Duan X, Shen H, Rathinam VA, Erickson LD, Fitzgerald KA, Choubey D. Aim2 deficiency stimulates the expression of IFN-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus. J Immunol 2010;185:7385–7393.
108. Kahlenberg JM, Thacker SG, Berthier CC, Cohen CD, Kretzler M, Kaplan MJ. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol 2011;187:6143–6156.
109. Tsai PY, Ka SM, Chang JM, Chen HC, Shui HA, Li CY, Hua KF, Chang WL, Huang JJ, Yang SS, Chen A. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med 2011;51:744–754.
110. Zhao J, Zhang H, Huang Y, Wang H, Wang S, Zhao C, Liang Y, Yang N. Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation. Int Immunopharmacol 2013;17:116–122.
111. Zhao J, Wang H, Huang Y, Zhang H, Wang S, Gaskin F, Yang N, Fu SM. Lupus nephritis: glycogen synthase kinase 3β promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice. Arthritis Rheumatol 2015;67:1036–1044.
112. Ka SM, Lin JC, Lin TJ, Liu FC, Chao LK, Ho CL, Yeh LT, Sytwu HK, Hua KF, Chen A. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Ther 2015;17:331.
113. Li M, Shi X, Qian T, Li J, Tian Z, Ni B, Hao F. A20 overexpression alleviates pristine-induced lupus nephritis by inhibiting the NF-κB and NLRP3 inflammasome activation in macrophages of mice. Int J Clin Exp Med 2015;8:17430–17440.
114. Yuan Y, Liu Z. Isoflurane attenuates murine lupus nephritis by inhibiting NLRP3 inflammasome activation. Int J Clin Exp Med 2015;8:17730–17738.
115. Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS. Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev 2011;63:641–683.
116. Gombault A, Baron L, Couillin I. ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol 2013;3:414
117. Franceschini A, Capece M, Chiozzi P, Falzoni S, Sanz JM, Sarti AC, Bonora M, Pinton P, Di Virgilio F. The P2X7 receptor directly interacts with the NLRP3 inflammasome scaffold protein. FASEB J 2015;29:2450–2461.
118. Karmakar M, Katsnelson MA, Dubyak GR, Pearlman E. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat Commun 2016;7:10555
119. Bours MJ, Dagnelie PC, Giuliani AL, Wesselius A, Di Virgilio F. P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci (Schol Ed) 2011;3:1443–1456.
120. Zhao J, Wang H, Dai C, Wang H, Zhang H, Huang Y, Wang S, Gaskin F, Yang N, Fu SM. P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum 2013;65:3176–3185.
121. Kahlenberg JM, Yalavarthi S, Zhao W, Hodgin JB, Reed TJ, Tsuji NM, Kaplan MJ. An essential role of caspase 1 in the induction of murine lupus and its associated vascular damage. Arthritis Rheumatol 2014;66:152–162.
122. Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N. Pathogenesis of ankylosing spondylitis - recent advances and future directions. Nat Rev Rheumatol 2017;13:359–367.
123. Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis 2011;70:1921–1925.
124. Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 2015;67:686–691.
125. Tsui FW, Tsui HW, Akram A, Haroon N, Inman RD. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet 2014;7:105–115.
126. Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis? insights into pathogenesis. Nat Rev Rheumatol 2016;12:81–91.
127. Bidad K, Gracey E, Hemington KS, Mapplebeck JCS, Davis KD, Inman RD. Pain in ankylosing spondylitis: a neuro-immune collaboration. Nat Rev Rheumatol 2017;13:410–420.
128. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford) 2014;53:650–657.
129. Carter ET, McKenna CH, Brian DD, Kurland LT. Epidemiology of Ankylosing spondylitis in Rochester, Minnesota, 1935-1973. Arthritis Rheum 1979;22:365–370.
130. Akkoc N, Khan MA. Overestimation of the prevalence of ankylosing spondylitis in the Berlin study: comment on the article by Braun et al. Arthritis Rheum 2005;52:4048–4049.
author reply 4049-4050.
131. Hanova P, Pavelka K, Holcatova I, Pikhart H. Incidence and prevalence of psoriatic arthritis, ankylosing spondylitis, and reactive arthritis in the first descriptive population-based study in the Czech Republic. Scand J Rheumatol 2010;39:310–317.
132. Bakland G, Nossent HC, Gran JT. Incidence and prevalence of ankylosing spondylitis in Northern Norway. Arthritis Rheum 2005;53:850–855.
133. Koko V, Ndrepepa A, Skënderaj S, Ploumis A, Backa T, Tafaj A. An epidemiological study on ankylosing spondylitis in southern Albania. Mater Sociomed 2014;26:26–29.
134. Kaipiainen-Seppanen O, Aho K, Heliovaara M. Incidence and prevalence of ankylosing spondylitis in Finland. J Rheumatol 1997;24:496–499.
135. Alamanos Y, Papadopoulos NG, Voulgari PV, Karakatsanis A, Siozos C, Drosos AA. Epidemiology of ankylosing spondylitis in Northwest Greece, 1983-2002. Rheumatology (Oxford) 2004;43:615–618.
136. Tan AL, Marzo-Ortega H, O'Connor P, Fraser A, Emery P, McGonagle D. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis 2004;63:1041–1045.
137. Kastbom A, Klingberg E, Verma D, Carlsten H, Forsblad-d'Elia H, Wesamaa J, Cedergren J, Eriksson P, Soderkvist P. Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis. Scand J Rheumatol 2013;42:465–468.
138. Son CN, Bang SY, Kim JH, Choi CB, Kim TH, Jun JB. Caspase-1 level in synovial fluid is high in patients with spondyloarthropathy but not in patients with gout. J Korean Med Sci 2013;28:1289–1292.
139. Kiripolsky J, McCabe LG, Kramer JM. Innate immunity in Sjögren's syndrome. Clin Immunol 2017;182:4–13.
140. Stefanski AL, Tomiak C, Pleyer U, Dietrich T, Burmester GR, Dörner T. The diagnosis and treatment of Sjögren's syndrome. Dtsch Arztebl Int 2017;114:354–361.
141. Malladi AS, Sack KE, Shiboski SC, Shiboski CH, Baer AN, Banushree R, Dong Y, Helin P, Kirkham BW, Li M, Sugai S, Umehara H, Vivino FB, Vollenweider CF, Zhang W, Zhao Y, Greenspan JS, Daniels TE, Criswell LA. Primary Sjögren's syndrome as a systemic disease: a study of participants enrolled in an international Sjögren's syndrome registry. Arthritis Care Res (Hoboken) 2012;64:911–918.
142. Tomiak C, Dorner T. Sjögren's syndrome. Current aspects from a rheumatological point of view. Z Rheumatol 2006;65:505–517.
143. Westhoff G, Zink A. Epidemiology of primary Sjörgren's syndrome. Z Rheumatol 2010;69:41–49.
144. Qin B, Wang J, Yang Z, Yang M, Ma N, Huang F, Zhong R. Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis. Ann Rheum Dis 2015;74:1983–1989.
145. Killedar SJ, Eckenrode SE, McIndoe RA, She JX, Nguyen CQ, Peck AB, Cha S. Early pathogenic events associated with Sjögren's syndrome (SjS)-like disease of the NOD mouse using microarray analysis. Lab Invest 2006;86:1243–1260.
146. Bulosan M, Pauley KM, Yo K, Chan EK, Katz J, Peck AB, Cha S. Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren's syndrome before disease onset. Immunol Cell Biol 2009;87:81–90.
147. Baldini C, Rossi C, Ferro F, Santini E, Seccia V, Donati V, Solini A. The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjögren's syndrome. J Intern Med 2013;274:480–489.
148. Niu L, Zhang S, Wu J, Chen L, Wang Y. Upregulation of NLRP3 inflammasome in the tears and ocular surface of dry eye patients. PLoS One 2015;10:e0126277
149. Manoussakis MN, Boiu S, Korkolopoulou P, Kapsogeorgou EK, Kavantzas N, Ziakas P, Patsouris E, Moutsopoulos HM. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum 2007;56:3977–3988.
150. Yamada A, Arakaki R, Kudo Y, Ishimaru N. Targeting IL-1 in Sjögren's syndrome. Expert Opin Ther Targets 2013;17:393–401.
151. Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S. Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren's syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol 2008;181:2898–2906.
152. Bombardieri M, Barone F, Pittoni V, Alessandri C, Conigliaro P, Blades MC, Priori R, McInnes IB, Valesini G, Pitzalis C. Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate. Arthritis Res Ther 2004;6:R447–R456.
153. Delaleu N, Immervoll H, Cornelius J, Jonsson R. Biomarker profiles in serum and saliva of experimental Sjögren's syndrome: associations with specific autoimmune manifestations. Arthritis Res Ther 2008;10:R22
154. Woods LT, Camden JM, Batek JM, Petris MJ, Erb L, Weisman GA. P2X7 receptor activation induces inflammatory responses in salivary gland epithelium. Am J Physiol Cell Physiol 2012;303:C790–C801.
155. Shin SM, Choi DK, Jung K, Bae J, Kim JS, Park SW, Song KH, Kim YS. Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nat Commun 2017;8:15090