title: HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection.
abstract: High-mobility group box-1 (HMGB1) protein, as one of the well-known damage-associated molecular pattern molecules (DAMPs), is enriched in chronic hepatitis B virus (HBV) infection and has a context-dependent role in autophagy, a highly conserved self-digestive process in response to environmental stress. Recent mouse studies indicate that autophagy is highly active in regulatory T (Treg)-cells. In the present study, we evaluated spontaneous and induced autophagy of peripheral Treg cells from 98 patients with chronic hepatitis B (CHB), by measuring levels of lipidated form of microtubule-associated light chain 3 (LC3-II, marker for closed autophagosomes) and observing autophagic vacuoles (AV) with transmission electron microscope. No significant difference was found in spontaneous autophagy of either Treg or CD4+naive cells when comparing CHB patients with healthy subjects, apart from CHB-Treg showed significantly higher autophagic activity after activation by anti-CD3-CD28 beads. Besides, incubation of CHB-Treg cells with CHB-serum greatly maintained their autophagic behaviour, which could be significantly diminished by blocking HMGB1 with the neutralizing antibody. Further, we characterized time- and dose-dependent effects by recombinant HMGB1 protein on autophagy of CHB-Treg cells. We also documented a significant up-regulation of HMGB1 and its receptors [toll-like receptor (TLR4), receptor for advanced glycation end-product (RAGE)] in both peripheral and intra-hepatic microenvironments of CHB patients. Moreover, the RAGE-extracellular regulated protein kinases (ERK) axis and rapamycin-sensitive components of mammalian target of rapamycin (mTOR) pathways were demonstratedin vitroto be involved in HMGB1-induced autophagy of Treg cells. Additionally, HMGB1-induced autophagy could maintain cell survival and functional stability of CHB-Treg cells. Our findings could open new perspectives in developing therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy.
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Fu-Ping
authors.initials: FP
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Si-Qi
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: She
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Sheng-di
authors.initials: SD
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Qi
authors.affiliation: Department of Hepatobiliary Surgery, Second People's Hospital, Nanjing Medical University, Wuxi, China.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China jiang.wei@zs-hospital.sh.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000378:metabolism; D001343:Autophagy; D016022:Case-Control Studies; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D024243:HMGB1 Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: autophagy; chronic hepatitis B; high-mobility group box-1; regulatory T-cells