Enhanced high-mobility group box 1 (HMGB1) modulates regulatory T cells (Treg)/T helper 17 (Th17) balance via toll-like receptor (TLR)-4-interleukin (IL)-6 pathway in patients with chronic hepatitis B
Enhanced high-mobility group box 1 (HMGB1) modulates regulatory T cells (Treg)/T helper 17 (Th17) balance via toll-like receptor (TLR)-4-interleukin (IL)-6 pathway in patients with chronic hepatitis B
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增强型高迁移率族蛋白 1 (HMGB1) 通过 Toll 样受体 (TLR)-4-白细胞介素 (IL)-6 通路调节慢性乙型肝炎患者的调节性 T 细胞 (Treg)/T 辅助细胞 17 (Th17) 平衡
DOI：
10.1111/jvh.12152
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发表时间：
2014-02-01
影响因子：
2.5
通讯作者：
Jiang, W.
中科院分区：
文献类型：
--
作者：
Li, J.;Wang, F. -P.;Jiang, W.
高迁移率组框1 （HMGB1）蛋白在急性和慢性肝炎中显著上调。然而，HMGB1在慢性乙型肝炎（CHB）患者中的免疫致病作用尚未阐明。在这项研究中，我们使用了36例慢性乙型脑出血患者，我们证明了HMGB1通过toll样受体(TLR)-4-白细胞介素(IL)-6途径调节调节性T （Treg）和辅助性T 17 （Th17）细胞之间的平衡的关键作用。慢性乙型肝炎患者血清HMGB1水平显著升高，并随着肝损伤、炎症和纤维化而升高。值得注意的是，HMGB1随着外周或肝内微环境中Treg/Th17细胞比例的降低而增加，这为HMGB1促进Th17反应而抑制Treg反应提供了线索。在体外研究中，用晚期CHB患者的血清构建血清池，而外周血单个核细胞（PBMC）池则用早期CHB患者的细胞构建。chb血清显著增强视黄酸相关孤儿受体-t (ort)，抑制CHB-PBMC中叉头盒P3 （Foxp3）的表达，这可以通过阻断HMGB1、TLR4或IL-6来逆转。此外，重组HMGB1 （rHMGB1）在CHB-PBMC中呈剂量依赖性上调RORt，下调Foxp3表达，同时增强TLR4和IL-6在CHB-PBMC中的表达。此外，HMGB1-TLR4-IL-6-Treg/Th17轴需要CD4和非CD4细胞之间的非接触相互作用。此外，rHMGB1下调CD4(+)CD25（+）细胞的抗炎蛋白，而上调CD4(+)CD25（-）细胞的促炎细胞因子。综上所述，CHB患者中富集的HMGB1通过TLR4-IL-6途径将Treg/Th17平衡转变为Th17优势，从而加剧肝损伤和炎症。
High-mobility group box 1 (HMGB1) proteins are substantially up-regulated in acute and chronic hepatitis. However, the immunopathogenic role of HMGB1 in patients with chronic hepatitis B (CHB) has not been elucidated. In this study, using a cohort of 36 CHB patients, we demonstrated a crucial role for HMGB1 to modulate balance between regulatory T (Treg) and T helper 17 (Th17) cells via the toll-like receptor (TLR)-4-interleukin (IL)-6 pathway. Serum HMGB1 levels were dramatically higher in CHB patients and increased along with liver injury, inflammation and fibrosis. Notably, HMGB1 increased along with decreased Treg/Th17 cells ratios in the periphery or intrahepatic microenvironment, which provides a clue for HMGB1 to favour Th17 responses whereas inhibit Treg responses. For in vitro studies, serum pools were constructed with serum from CHB patients at an advanced stage, whereas peripheral blood mononuclear cells (PBMC) pools were constructed with cells from those at an early stage. CHB-serum significantly enhanced retinoic acid-related orphan receptor-t (RORt), whereas they inhibited forkhead box P3 (Foxp3) expression in CHB-PBMC, which could be reversed by blocking of HMGB1, TLR4, or IL-6. Besides, recombinant HMGB1 (rHMGB1) dose-dependently up-regulated RORt whereas down-regulated Foxp3 expression in CHB-PBMC, and meanwhile, rHMGB1 enhanced TLR4 and IL-6 expression in CHB-PBMC. Moreover, the axis of HMGB1-TLR4-IL-6-Treg/Th17 required noncontact interactions between CD4 and non-CD4 cells. In addition, rHMGB1 down-regulated anti-inflammatory proteins on CD4(+)CD25(+) cells whereas up-regulated pro-inflammatory cytokines in CD4(+)CD25(-) cells. In summary, enriched HMGB1 in CHB patients shifts Treg/Th17 balance to Th17 dominance via the TLR4-IL-6 pathway, which exacerbates liver injury and inflammation.