HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection
HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection
复制标题
HMGB1诱导的自噬：慢性乙型肝炎病毒感染期间维持Treg功能的新途径
DOI：
10.1042/cs20160704
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发表时间：
2017-03-01
期刊：
影响因子：
6
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Cheng, Li-sha;Li, Jing;Jiang, Wei
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) infec-tion 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 spontan-eous and induced autophagy of peripheral Treg cells from 98 patients with chronic hep-atitis 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 electronmicroscope. No significant difference was found in spontaneous autophagy of either Treg or CD4(+) naive cells when comparing CHB patients with healthy sub-jects, 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 docu-mented 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 rapamy-cin (mTOR) pathways were demonstrated in vitro to be involved in HMGB1-induced auto-phagy 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 de-veloping therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy.
