Background

CD4⁺CD25⁺FoxP3⁺ 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.

中文翻译：

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HMGB1通过抑制Treg的活性和功能加重了脂多糖诱导的急性肺损伤。

背景

CD4 ⁺ CD25 ⁺ FoxP3 ⁺ T辅助细胞（Tregs）是CD4 ⁺ T辅助细胞的一个亚组，是通过接触依赖性抑制或释放抗炎细胞因子（包括白介素10（ IL-10）和转化生长因子（TGF-β）。HMGB1（高迁移率族1盒蛋白）被鉴定为核非组蛋白DNA结合染色体蛋白，它参与ALI中肺炎症反应和病理过程的调节。先前的研究表明，Tregs过表达HMGB1识别受体。但是，HMGB1与ALI中Treg的相互作用仍不清楚。

目的

调查HMGB1是否通过抑制Tregs的免疫抑制功能来加重ALI。

方法

抗HMGB1抗体和重组小鼠HMGB1（rHMGB1）在脂多糖（LPS）诱导的ALI小鼠和极化的LPS引发的Treg中进行了体外给药。用或不用rHMGB1预先刺激的Treg被过继转移到ALI小鼠中，并被白喉毒素（DT）消耗掉。对于共培养实验，首先在有或没有rHMGB1或抗HMGB1抗体的情况下预先刺激分离的Treg，然后在LPS刺激下将它们与骨髓巨噬细胞（BMM）共培养。

结果

Treg可防止急性肺部病理损伤。HMGB1通过以下方式调节Treg的抑制功能：减少细胞数量和Treg的活性，从Treg分泌抗炎细胞因子（IL-10，TGF-β），从CD4产生IL-2。⁺ T细胞和CD11c ⁺ DC，以及巨噬细胞的M2极化，以及诱导巨噬细胞的促炎反应。

结论

HMGB1可以通过抑制Tregs的活性和功能来加重LPS诱导的ALI。