Objectives

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe form of inflammatory lung disease. Its development and progression are regulated by cytokines. The purpose of this study was to determine the effects of HMGB1 involved in the regulation of Treg cells and IL-35.

Methods

A cecal ligation and puncture (CLP)-induced ALI model was used to investigate the changes in IL-35, Tregs, and the expression of RAGE and caspase-11 after HMGB1 inhibition (glycyrrhizin was used as an inhibitor of HMGB1). CD4+ naïve T cells sorted from C57BL/6 mice spleens were cultured to explore the role of HMGB1 in the differentiation from CD4+ naïve T cells to Tregs.

Results

HMGB1 promoted lung injury and uncontrolled inflammation in the CLP mouse model. HMGB1, NF-κB p65, RAGE, and caspase-11 expression in the lungs of CLP mice decreased significantly after pretreatment with glycyrrhizin. We found that the Treg proportion and IL-35 expression were upregulated in the serum and lung of CLP mice after inhibiting HMGB1. In our in vitro experiments, we found that recombinant HMGB1 significantly suppressed the proportion of CD4+CD25+FOXP3+Tregs differentiated from CD4+ naïve T cells.

Conclusions

The inhibition of HMGB1 increased the proportion of Treg and expression of IL-35 and alleviated lung injury in the CLP-induced ALI model. Furthermore, inhibition of HMGB1 reduced caspase-11-dependent pyroptosis in the lungs of the CLP-induced ALI model.

中文翻译：

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HMGB1通过调节Naïve CD4+ T细胞分化并加重急性肺损伤中Caspase-11依赖性焦亡来抑制IL-35的表达

 目标

急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是一种严重的炎症性肺部疾病。其发生和进展受细胞因子的调节。本研究的目的是确定 HMGB1 参与调节 Treg 细胞和 IL-35 的作用。

 方法

采用盲肠结扎穿刺（CLP）诱导的ALI模型，研究HMGB1抑制（甘草甜素作为HMGB1抑制剂）后IL-35、Tregs以及RAGE和caspase-11表达的变化。培养从 C57BL/6 小鼠脾脏分选的 CD4+ 幼稚 T 细胞，以探讨 HMGB1 在 CD4+ 幼稚 T 细胞分化为 Tregs 中的作用。

 结果

HMGB1 在 CLP 小鼠模型中促进肺损伤和不受控制的炎症。甘草甜素预处理后，CLP小鼠肺部HMGB1、NF-κB p65、RAGE和caspase-11表达显着降低。我们发现抑制HMGB1后，CLP小鼠血清和肺中Treg比例和IL-35表达上调。在我们的体外实验中，我们发现重组HMGB1显着抑制了从CD4+幼稚T细胞分化而来的CD4+CD25+FOXP3+Tregs的比例。

 结论

在 CLP 诱导的 ALI 模型中，抑制 HMGB1 会增加 Treg 的比例和 IL-35 的表达，减轻肺损伤。此外，抑制 HMGB1 可减少 CLP 诱导的 ALI 模型肺部的 caspase-11 依赖性细胞焦亡。