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 demonstrated in vitro to 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.
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Phase contrast microscopy showing primary human mesangial cells in culture. Quantification of cell area showed that exposure of mesangial cells to the pro-fibrotic growth factor (TGF-β1) induced morphological cell expansion and hypertrophy, which was reversed following the overexpression of miR-378. Interestingly, transfection of a miR-378 inhibitor induced the expansion of mesangial cells, highlighting the regulatory role of miR-378 in mesangial hypertrophy. Please see the article by Wang et al. (pages 411-423).
Research Article|
February 15 2017
HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection
Li-sha Cheng;
Li-sha Cheng
1
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Jing Li;
Jing Li
1
†Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China
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Yun Liu;
Yun Liu
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Fu-ping Wang;
Fu-ping Wang
‡Department of Gastroenterology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
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Si-qi Wang;
Si-qi Wang
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Wei-min She;
Wei-min She
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Sheng-di Wu;
Sheng-di Wu
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Xiao-long Qi;
Xiao-long Qi
§Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Yong-ping Zhou;
Yong-ping Zhou
║Department of Hepatobiliary Surgery, Second People's Hospital, Nanjing Medical University, Wuxi, China
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Wei Jiang
*Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
Correspondence: Wei Jiang (email [email protected])
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Publisher: Portland Press Ltd
Received:
September 09 2016
Revision Received:
December 29 2016
Accepted:
January 12 2017
Accepted Manuscript online:
January 12 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (5): 381–394.
Article history
Received:
September 09 2016
Revision Received:
December 29 2016
Accepted:
January 12 2017
Accepted Manuscript online:
January 12 2017
Citation
Li-sha Cheng, Jing Li, Yun Liu, Fu-ping Wang, Si-qi Wang, Wei-min She, Sheng-di Wu, Xiao-long Qi, Yong-ping Zhou, Wei Jiang; HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection. Clin Sci (Lond) 1 March 2017; 131 (5): 381–394. doi: https://doi.org/10.1042/CS20160704
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