Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Alirezaei, Mehrdad; Fox, Howard S.; Flynn, Claudia T.; Moore, Craig S.; Hebb, Andrea L.O.; Frausto, Ricardo F.; Bhan, Virender; Kiosses, William B.; Whitton, J. Lindsay; Robertson, George S.; Crocker, Stephen J.

doi:10.4161/auto.5.2.7348

Cited by 134 publications

(113 citation statements)

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“…ATG5 is signifi cantly elevated in T-cells in MS lesions and EAE mice compared to controls. The increase of autophagy in T-cells may promote their survival, contributing to the pathogenesis of MS [53] . Immune-related GTPase M1 is highly expressed in MS lesions in the CNS and EAE models, and contributes to the pathogenesis of MS by increasing the survival of autoreactive CD4 + T-cells [17] .…”

Section: Autoreactive T-cell Regulation By Autophagymentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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Section: Autoreactive T-cell Regulation By Autophagymentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Section: Introductionmentioning

confidence: 99%

“…Recently, various autophagic functions have been recognized in innate and adaptive immunity, including pathogen clearance, inflammasome regulation, and maintenance of tolerance [2,3]. The observations Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn of the autophagic functions that trigger or exacerbate autoimmunity show that autophagy participates in the pathogenesis of autoimmune disorders, such as systemic lupus erythematosus (SLE) [4][5][6].SLE is a potentially fatal autoimmune disease that is characterized by B-cell hyperactivation and production of autoantibodies that mainly target nuclear components [7]. Of note, B cells play a central role in the pathogenesis of SLE through the production of pathogenic autoantibodies [8,9].…”

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confidence: 99%

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

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Systemic lupus erythematosus (SLE) is Keywords: Autophagy B cells Interferon-α STS-1 Systemic lupus erythematosusAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy, conventionally referred to as autophagy, is a highly conserved lysosome-mediated catabolic process in which cytoplasmic contents are degraded and recycled [1]. Recently, various autophagic functions have been recognized in innate and adaptive immunity, including pathogen clearance, inflammasome regulation, and maintenance of tolerance [2,3]. The observations Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn of the autophagic functions that trigger or exacerbate autoimmunity show that autophagy participates in the pathogenesis of autoimmune disorders, such as systemic lupus erythematosus (SLE) [4][5][6].SLE is a potentially fatal autoimmune disease that is characterized by B-cell hyperactivation and production of autoantibodies that mainly target nuclear components [7]. Of note, B cells play a central role in the pathogenesis of SLE through the production of pathogenic autoantibodies [8,9]. Enhanced autophagic activities have been observed in B cells from SLE patients and NZB/W F1 mice [5]. Studies have increasingly demonstrated that autophagy C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2378 Guanjun Dong et al. Eur. J. Immunol. 2015. 45: 2377-2388 is involved in B-cell development, homeostasis, activation, and antibody response [10,11]. Because B cells are a major player in SLE, autophagy-mediated modulation of B cells can directly influence the pathophysiology of SLE. In fact, the contribution of autophagy to the pathogenesis of SLE has been supported by the beneficial effects of autophagy modulating molecules on disease development in SLE patients and lupus-prone mice, such as rapamycin and P140 peptide [12,13]. Given that the autophagy pathway can be considered as an effective therapeutic target in the treatment of SLE, the exploration of the enhanced autophagic activity mechanism of B cells during SLE is urgently needed. Autophagy can be provoked by host-derived cytokines, IFN-I/II or pattern recognition receptors in many cell types [2,14,15]. However, to date, the enhanced autophagic activity mechanism in SLE B cells remains unknown, although BCR ligands have been shown to induce autophagy in B cells [16,17]. Of note, IFN-α, a central cytokine in the pathogenesis of SLE, can induce and accelerate SLE symptoms in patients and mice [18]. Importantly, B cells display a significant IFN-I inducible gene signature in SLE patients [19] and IFN-α impacts B-cell functions through a variety of mechanisms, such as TLR7 expression, differentiation, and class-switch recombination [20][21][22]. Importantly, IFN-α provokes autophagy in many different cell types and JAK1-STAT1 signaling plays an absolutely necessary role in this process [23]. However, it remains unknown whether IFN-α can induce autophagy in primary human and murine B cells.ST...

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“…Des facteurs génétiques ou environnementaux modifiant l'activité autophagique pourraient ainsi être impliqués dans certaines pathologies. La première étude s'intéressant à l'activité autophagique des lymphocytes lors de dysfonctionnements immunitaires décrit une augmentation de l'expression de la protéine ATG5 dans les LT qui infiltrent les lésions observées dans la sclérose en plaques (SEP) [41]. L'absence d'autophagie dans les LT diminue ainsi les symptômes de la pathologie dans un modèle murin de SEP [25], l'amélioration clinique étant liée à une baisse du nombre de lymphocytes de type Th1.…”

Section: Autophagie Des Lymphocytes Et Physiopathologieunclassified