高迁移率族蛋白 B1 通过抑制 Tregs 的活性和功能加重脂多糖诱导的急性肺损伤。
HMGB1 aggravates lipopolysaccharide-induced acute lung injury through suppressing the activity and function of Tregs.
机构信息
Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China.
Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China.
出版信息
Cell Immunol. 2020 Oct;356:104192. doi: 10.1016/j.cellimm.2020.104192. Epub 2020 Aug 7.
BACKGROUND
CD4CD25FoxP3 T helper cells (Tregs), a subgroup of CD4 T helper cells, are critical effectors that protect against acute lung injury (ALI) by contact-dependent suppression or releasing anti-inflammatory cytokines including interleukin-10 (IL-10), and transforming growth factor (TGF-β). HMGB1 (High mobility group box 1 protein) was identified as a nuclear non-histone DNA-binding chromosomal protein, which participates in the regulation of lung inflammatory response and pathological processes in ALI. Previous studies have suggested that Tregs overexpresses the HMGB1-recognizing receptor. However, the interaction of HMGB1 with Tregs in ALI is still unclear.
OBJECTIVE
To investigate whether HMGB1 aggravates ALI by suppressing immunosuppressive function of Tregs.
METHODS
Anti-HMGB1 antibody and recombinant mouse HMGB1 (rHMGB1) were administered in lipopolysaccharide (LPS)-induced ALI mice and polarized LPS-primed Tregs in vitro. The Tregs pre-stimulated with or without rHMGB1 were adoptively transferred to ALI mice and depleted by Diphtheria toxin (DT). For coculture experiment, isolated Tregs were first pre-stimulated with or without rHMGB1 or anti-HMGB1 antibody, then they were cocultured with bone marrow-derived macrophages (BMMs) under LPS stimulation.
RESULTS
Tregs protected against acute lung pathological injury. HMGB1 modulated the suppressive function of Tregs as follows: reduction in the number of the cells and the activity of Tregs, the secretion of anti-inflammatory cytokines (IL-10, TGF-β) from Tregs, the production of IL-2 from CD4 T cells and CD11c DCs, and the M2 polarization of macrophages, as well as inducing proinflammatory response of macrophages.
CONCLUSIONS
HMGB1 could aggravate LPS induced-ALI through suppressing the activity and function of Tregs.
背景
CD4CD25FoxP3+ T 辅助细胞（Tregs）是 CD4+ T 辅助细胞的一个亚群，通过接触依赖性抑制或释放抗炎细胞因子（包括白细胞介素-10（IL-10）和转化生长因子-β（TGF-β）），是防止急性肺损伤（ALI）的关键效应物。高迁移率族蛋白 B1（HMGB1）被鉴定为一种核非组蛋白 DNA 结合染色体蛋白，参与调节肺炎症反应和 ALI 的病理过程。先前的研究表明，Tregs 过度表达 HMGB1 识别受体。然而，HMGB1 与 ALI 中的 Tregs 的相互作用仍不清楚。
目的
研究 HMGB1 是否通过抑制 Tregs 的免疫抑制功能加重 ALI。
方法
在脂多糖（LPS）诱导的 ALI 小鼠和体外极化的 LPS 诱导的 Tregs 中给予抗-HMGB1 抗体和重组小鼠 HMGB1（rHMGB1）。用白喉毒素（DT）耗竭预先用或不用 rHMGB1 刺激的 Tregs 后，将其过继转移到 ALI 小鼠中。对于共培养实验，首先用 rHMGB1 或抗-HMGB1 抗体预刺激分离的 Tregs，然后在 LPS 刺激下与骨髓来源的巨噬细胞（BMMs）共培养。
结果
Tregs 可保护急性肺病理损伤。HMGB1 调节 Tregs 的抑制功能，具体表现为：Tregs 细胞数量和活性减少，Tregs 细胞抗炎细胞因子（IL-10、TGF-β）分泌减少，CD4+T 细胞和 CD11c DCs 产生 IL-2 减少，巨噬细胞 M2 极化减少，以及诱导巨噬细胞的促炎反应。
结论
HMGB1 可通过抑制 Tregs 的活性和功能加重 LPS 诱导的 ALI。
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