HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury.
HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury.
复制标题
HMGB1/TLR4 信号传导影响急性肺损伤中的调节性 T 细胞
DOI：
10.2147/jir.s302967
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发表时间：
2021
影响因子：
4.5
通讯作者：
Fang H
中科院分区：
文献类型：
--
作者：
Zhou M;Zhang Y;Tang R;Liu H;Du M;Gao Z;Ji Z;Fang H
研究背景高迁移率族蛋白B1（HMGB 1）是细胞损伤相关的分子模式，TLR 4被认为是HMGB 1的受体。调节性T细胞（Regulatory T cells，Tcells）在感染性疾病中起着至关重要的作用。HMGB 1在TGFAP调节中的作用引起了极大的兴趣。方法检测58例急性肺损伤（ALI）患者和36例健康志愿者血清中HMGB 1和Treg的含量。分析了这些参数与病情严重程度的相关性。WT和TLR 4-/-小鼠通过腹膜内注射施用HMGB 1。48小时后，处死小鼠。观察肺组织形态学变化及肺湿/干比值。取脾细胞，分离CD 4 + CD 25 + T淋巴细胞，检测FOXP 3、CTLA-4的表达及细胞因子的释放。将CD 4 + CD 25 + T细胞与效应T细胞共培养，检测其抑制效应及细胞因子的释放。结果ALI患者血浆HMGB 1水平明显升高，CD 4 + CD 25 + CD 127 low T细胞亚群明显降低。在小鼠模型中，与对照组相比，WT和TLR 4-/-组中HMGB 1滴注后肺损伤显著增加。肺湿/干比、BALF中TNF-α和IL-1β含量均显著升高，且WT小鼠的严重程度高于TLR 4-/-小鼠。与WT小鼠相比，TLR 4-/-小鼠中FOXP 3和CTLA-4的表达显著增加，并且与IL-10和TGF-β水平的类似趋势相关（p<0.05）。在与效应T细胞共培养中，与来自WT小鼠的TcR相比，从TLR 4-/-小鼠分离的TcR表现出降低的IL-2和IFN-γ以及增加的IL-4水平。观察到TLR 4-/-CD 4 + CD 25 + Treg细胞向Th 2细胞的极化增加。结论在HMGB 1诱导的肺损伤中，HMGB 1通过TLR 4影响FOXP 3和CTLA-4的表达，从而降低Treg细胞的免疫抑制功能。
Background High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest. Methods Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected. Results Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p<0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed. Conclusion In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.