Pathogenic Role of Autophagy in Rheumatic Diseases

Yun Jung Choi; Wan-Hee Yoo

doi:10.4078/jrd.2016.23.4.202

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Choi and Yoo: Pathogenic Role of Autophagy in Rheumatic Diseases

Review Article

J Rheum Dis 2016;23(4):202-211.

Published online: 31 October 2016

DOI: https://doi.org/10.4078/jrd.2016.23.4.202

Pathogenic Role of Autophagy in Rheumatic Diseases

Yun Jung Choi, Wan-Hee Yoo

Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea

Corresponding to: Wan-Hee Yoo, Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea. E-mail: ywhim@jbnu.ac.kr

Received 7 July 2016 Revised 2 August 2016 Accepted 2 August 2016

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Autophagy is a principle catabolic process mediated by lysosomes in eukaryotic cells. This is an intracellular homeostatic mechanism crucial for degradation in acidic lysosomal compartments of waste components from the cytoplasm. Autophagy research was initially focused on its degradation mechanism, but focus is now shifting to its effects on immunity. It contributes to detection and removal of pathogens as well as regulation of inflammasomes and neutrophil extracellular traps. Moreover, it is pivotal in antigen presentation and immune cell maturation, survival and homeostasis. The importance of autophagic pathways in normal and dysregulated immunity has become increasingly recognized in the past several years. Dysregulation of the autophagic pathway is implicated in the pathogenesis of several rheumatic diseases. In this review, we summarize the immunological function of autophagy in innate and adaptive immunity, and the functions of autophagy in the pathogenesis of rheumatic diseases.

Keywords: Autophagy, Immunity, Rheumatic diseases, Systemic lupus erythematosus, Rheumatoid arthritis

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Figure 1.

Autophagic pathway. The autophagy pathway is induced by inactivation of mTOR complex. Starvation or energy ex-haustion inhibits mTOR complex, it enables ULK complex to be dissociated from mTOR complex. The stimulated ULK complex translocates to the ER, and activates class III PI3K complex. The PI3P, which is essential for autophagosomal membrane nucleation, is formed by activated class III PI3K complex. The phagophore expansion and closure mediated through conversion of LC3-I to LC3-II occurred with the help of ATG7-induced, ATG5-ATG12 complex mediated lipidation. After formation of autophagosome, it fuses with lysosome to form autolysosome and sequestered materials are degradaed by lysosomal hydrolase. Adapted from Figure 1 in the article of Levine et al. [20] (Nature 2011;469:323-35). mTOR: mammalian target of rapamycin, ULK: UNC-51-like kinase, ER: endoplasmic reticulum, PI3K: phosphatidylinositol 3-kinase, PI3P: phosphatidylinositol-3-phosphate, LC: light chain, ATG: au-tophagy-related protein, DEPTOR: DEP domain containing mTOR-interacting protein, FIP200: focal adhesion kinase family inter-acting protein of 200 kDA, Gβ L/mLST8: G protein β subunit-like protein, PRAS40: protein-rich AKT substrate 40 kDA, RAPTOR: regulatory associated protein of mTOR, PIK3C3: PI3K catalytic subunit type 3, PIK3R4: PI3K regulatory subunit 4, UVRAG: UV radiation resistance associated gene protein.

Table 1.

Autophagic defect of immune cells in the pathogenesis of rheumatic disease

Disease	Cell or tissue	Model	Dysregulation of autophagy	Ref.
SLE	T lymphocyte	Human	Resistant to autophagic induction	57
			Upregulation of genes negatively regulating autophagy
		Mice	Autophagy increased	56
	B lymphocyte	Human & mice	No difference	56
			STS-1 increased→ JAK-STAT signaling increased→ IFN-induced autophagy increased	83
			Autophagy increased in early developmental stage of B cell	84
			Autophagy deficient B cell: failure of differentiation into plasma cell
		Mice	CD19-Cre-Atg5 ^f/f: normal inflammatory response	60
	Macrophage	Human & mice	Higher expression of Atg	85
			Beclin-1 knockdown: anti-dsDNA antibody, proteinuria, IL-6 and TNF-α decreased
RA	Synovial fibroblast	Human	Autophagy increased and apoptosis decreased: Beclin-1, LC 3 increased and miR-30a decreased	68
			Dual role of autophagy	69
			– Cytoprotective in proteasome inhibition-induced apoptosis
			– Cell death increased under the condition of severe ER stress
			Higher level of autophagy induced by ER stress→ PAD4 activation	67
			→ protein citrullination increased
			Positive correlation between autophagy and anti-CCP Antibodies in early naïve RA patients
		Mice	ER stress-induced autophagy increased	75
			Beclin-1 siRNA: autophagy decreased, cell death increased
	Osteoclast	Human & mice	Beclin-1 and Atg 7 increased	70
			Overexpression of Beclin-1: osteoclastogenesis increased
	T lymphocyte	Human	Autophagy decreased	86
SSc	Skin biopsy specimen	Human	Autophagy increased	76
	Fibroblast		Autophagy decreased	77
	Stromal cell	Mice	Autophagy increased in caveolin-deficient mice	79
PsA	Dendritic cell	Human	ATG16L1 increased	80
AS	Ileal biopsy specimen	Human	ATG16L1, ATG5 and ATG12 increased	82
			HSPA8, HSP90AA1 decreased

SLE: systemic lupus erythematosus, STS-1: suppressor of T-cell receptor signaling 1, JAK-STAT: Janus kinase– signal transducer and activator of transcription, IFN: interferon, Atg: autophagy-related gene, IL: interleukin, TNF-α: tumor necrosis factor-α, RA: rheumatoid arthritis, LC: light chain, ER: endoplasmic reticulum, siRNA: small interfering RNA, SSc: systemic sclerosis, PsA: psoriatic arthritis, ATG: autophagy-related protein, AS: ankylosing spondylitis, HSP: heat shock protein.

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