Researches on inflammation have been greatly facilitated by the discovery and characterization of innate immune receptors such as TLR, NLR, RLR or CLR. Role of TLR, the first immune receptor characterized, in type 2 diabetes, obesity or atherosclerosis has been suggested in several previous papers (1,2) which can explain chronic inflammation in type 2 diabetes (3,4). In contrast, the role for NLR in metabolic disorders is being recognized only recently. Among NLRs comprising more than 20 members, NLRP family members may be particularly relevant for metabolic disorders because NLRP, as a constituent of inflammasome, plays a vital role in the maturation and release of IL-1β (5). IL-1β has been implicated in both type 1 and type 2 diabetes (6-8), and inflammasome is an essential component of the intracellular machinery for IL-1β induction and maturation in response to exogenous or endogenous stimuli ("danger signal") (9).

Activation of NLRP has been intensely investigated. However, certain steps of NLRP activation are not clearly understood. After contact with DAMP (death-associated molecular pattern) or PAMP (pathogen-associated molecular pattern), NLRP self-oligomerizes through NACHT domain to form a high-molecular weight flatform. In the case of NLRP2 or NLRP3, they bind to an adaptor protein called ASC which has both PYD domain and CARD domain, and sometimes is also called PYCARD. Upon stimulation, PYD domain of NLRP2 or 3 associates with PYD domain of ASC through another homotypic interaction. Then, CARD domain of ASC entices CARD domain of procaspase-1. Homotypic clustering of procaspase-1 induces self-cleavage of the 'pro' domain and formation of the active caspase-1 p10/p20 tetramer, which then processes pro-IL-1β to IL-1β by cleavage of another 'pro' sequence (10) (Fig. 1). While the molecular mechanism downstream of NLRP oligomerization is well characterized, intracellular sequence leading to oligomerization of NLRP remains to be elucidated. Cytosolic delivery of PAMP through pannexin-1 hemichannel interacting with P2X7 ATP receptor, K⁺ efflux, lysosomal injury and reactive oxygen species (ROS) formation have been implicated as the proximal events leading to NLRP oligomerization (10,11) (Fig. 1). Recent papers have presented evidence suggesting the role of mitochondria as a source of ROS leading to NLRP stimulation (12,13). A recent paper claimed the role of ROS in the dissociation of TXNIP from thioredoxin leading to its binding to NLRP3 and inflammasome activation (14). An interesting point in the relationship between inflammasome and metabolism is that glyburide, a well-known drug of sulfonylurea class for type 2 diabetes inhibits NLRP3 stimulation, which is independent of its effect on ATP-sensitive K_ATP channel (15). Effect of glyburide on sepsis has also been reported. Considering the proposed role of NLRP3 activation in type 2 diabetes and metabolic syndrome (see below), it will be an intriguing question how much of the effect of glyburide on type 2 diabetes would be explained by NLRP3 inhibition. While the role for NLRP3 is most prominent in the development of inflammation, its role in the protection of epithelial cells has also been demonstrated (16), which is reminiscent of the previously reported role of TLR in the protection of intestinal epithelial cells (17).

Several papers have implicated diverse arms of innate immunity such as TLR, eosinophils or mast cells in insulin resistance (4,18,19). A recent paper reported the role of NLRP3 in obesity-induced inflammation and insulin resistance. In that paper, positive correlation between IL-1β (or NLRP3) mRNA expression and body weight of calorie-restricted mice was shown. Improved glucose tolerance was also found in obese mice with targeted disruption of NLRP3. IL-1β release in response to ceramide in conjunction with LPS was also abrogated in NLRP3-knockout macrophages (20). However, it is still not clear if C2 ceramide used in that experiment could represent lipids associated with obesity in vivo. It also remains to be clarified what lipid intermediates or metabolites are able to activate inflammasome in obese subjects.

A recent paper reported the expression of NLRP3, ASC and caspase-1 in islet cells. Decreased IL-1β release from NLRP3-knockout islet cells was also shown. NLRP3-knockout mice showed improved glucose profile after high-fat diet, which was ascribed to the attenuated IL-1β release from islet cells of NLRP3-knockout mice (14). Hyperglycemia-induced IL-1β release was also ascribed to increased ROS in response to hyperglycemia, induction of TXNIP and subsequent activation of NLRP3. However, it is not clear whether the source of IL-1β from islet cells is β-cells or immune cells in islets such as macrophages. Altered glucose metabolism in TXNIP-knockout mice might be also due to causes other than NLRP3 activation (21).

A recent report showed activation of NLRP3 by islet amyloid polypeptide (IAPP). Human diabetes and murine diabetes differ from each other in several points. One of the fundamental differences between them is frequent deposition of amyloid in islets of human type 2 diabetes but not in those of murine diabetes. Such a difference is due to the difference in amino acid sequence of IAPP. Human IAPP, the major component of islet amyloid, is amyloidogenic while murine one is not, which is attributable to the difference in their amino acid sequences. Masters et al. showed that human-type IAPP is able to induce NLRP3 activation and IL-1β release from dendritic cells or macrophages primed with LPS or minimally modified LDL (mmLDL), an agonist for TLR4 (22). Such results are similar to the activation of NLRP3 of microglial cells by amyloid-β via lysosomal injury (23); however, the role of TXNIP was not evident in IAPP-induced NLRP3 activation.

Atherosclerosis is also a well-known metabolic disease that has prominent inflammatory features. Role of innate immunity in the pathogenesis of atherosclerosis has been demonstrated in several TLR- or MyD88-knockout animals (3). Recent papers showed the role of NLRP3 activation by cholesterol crystals in the development of atherosclerosis (24) (Fig. 1). Lysosomal injury after phagocytosis of cholesterol crystals appears to be responsible for the activation of NLRP3. Besides cholesterol crystal, the role for mmLDL crystal in the priming of cells for NLRP3 activation was also suggested. In that case, mmLDL may be able to act as both signal 1 (priming signal) and signal for NLRP3 activation (24). Gout is also one of the classical examples related to NLRP3 activation. Gout is, in fact, one of the first metabolic diseases that involve activation of inflammasome. Crystals of monosodium urate and calcium pyrophosphate dehydrate were identified as the signals that are capable of NLRP3 activation in gout and pseudogout, respectively (25) (Fig. 1).

Type 1 diabetes is a well-known autoimmune disease that is characterized by a specific adaptive immunity against β-cell antigens. However, innate immunity plays a crucial role in the establishment of specific B- and T-cell immunity and its maintenance (26,27). We have reported that TLR, particularly TLR2, plays a critical role in the priming of naïve diabetogenic T cells in the pancreatic lymph nodes by sensing β-cell death (28) that occurs physiologically during the organogenesis of the pancreas (27). A recent study also showed possible role of innate immunity other than TLR in the development of type 1 diabetes by demonstrating the development of type 1 diabetes in MyD88-knockout NOD mice when they were rendered germ-free (29). However, it is not clear which types of innate immune receptors are involved in the development of autoimmunity in those MyD88-knockout mice. It is also not known which types of innate immunity play roles in the apparent disease inhibition by intestinal microbiota in those mice. The role for NLRP3 or NLR has not been demonstrated in the pathogenesis of type 1 diabetes. Further studies will be necessary to understand the disease-promoting or -inhibitory activity of NLR in type 1 diabetes.

Pathogenetic role of innate immunity is being generally appreciated in diabetes and metabolism that had been considered as pure metabolic disorders. TLR was the first innate immune receptors that have been studied in those diseases. Recent studies have shown important roles of non-TLR innate immune receptors, particularly NLRP3 in diverse metabolic disorders such as diabetes, atherosclerosis, obesity and gout. Further studies will be necessary to identify endogenous or exogenous ligands or activating signals for innate immune receptors involved in the pathogenesis of such diseases and to develop therapeutic agents based on the novel immunological principles.