Immune Regulation of Toll-Like Receptor 2 Engagement on CD4(+) T Cells in Murine Models of Malignant Pleural Effusion
Immune Regulation of Toll-Like Receptor 2 Engagement on CD4(+) T Cells in Murine Models of Malignant Pleural Effusion
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在恶性胸腔积液的小鼠模型中，Toll 样受体 2 对 CD4 T 细胞的免疫调节。
DOI：
10.1165/rcmb.2015-0396oc
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发表时间：
2017
影响因子：
6.4
通讯作者：
Shi Huan-Zhong
中科院分区：
文献类型：
--
作者：
Wu Xiu-Zhi;Zhou Qiong;Lin Hua;Zhai Kan;Wang Xiao-Juan;Yang Wei-Bing;Shi Huan-Zhong
Toll样受体(TLR)2在包括微生物产物、内毒素和一些细胞外基质分子在内的多种配体的感测中具有广为人知的作用，但它在恶性胸腔积液(MPE)发生发展中的作用尚不清楚。本研究旨在探讨TLR2信号在MPE发生发展中的作用，并明确TLR2的作用机制。比较TLR2−/−小鼠和野生型(WT)小鼠MPE的发育情况。探讨TLR2对MPE患者辅助性T细胞(Th17)、Th9细胞和Th2细胞分化的影响。并探讨了TLR2对MPE小鼠存活的影响机制。TLR2−/−小鼠的MPE体积小于WT小鼠，且携带MPE的TLR2−/−小鼠的存活时间长于WT小鼠。在MPE中，Th17细胞TLR2缺乏增加，TLR2活化降低，而TLR2信号转导对Th2细胞的作用相反。TLR2−/−小鼠外周血中Th9细胞数增加，但不受TLR2信号转导的影响。腹腔注射抗IL-17单抗、抗IL-9单抗或重组小鼠IL-4可加速TLR2−/−小鼠的死亡，且TLR2−/−小鼠的存活时间明显短于WT小鼠。我们首次证明，TLR2信号通过直接抑制Th17细胞分化和直接促进Th2细胞分化，以及通过IL-17依赖机制间接抑制Th9细胞分化，从而促进MPE的发生和加速MPE小鼠的死亡。
Toll-like receptor (TLR) 2 has a well-known role in sensing multiple ligands that include microbial products, endotoxin, and some extracellular matrix molecules; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE and to define the underlying mechanisms by which TLR2 works. Development of MPE was compared betweenTLR2−/−and wild-type (WT) mice. The effect of TLR2 on differentiation of T helper type 17 (Th17), Th9, and Th2 cells in MPE was explored. The mechanisms of TLR2 on survival of mice bearing MPE were also investigated. MPE volume inTLR2−/−mice was lower than that in WT mice, and the survival ofTLR2−/−mice bearing MPE was longer than that of WT mice. TLR2 deficiency increased, and TLR2 activation decreased, Th17 cells in MPE, whereas TLR2 signaling showed the contrary effects on Th2 cells. Th9 cells were increased in MPE ofTLR2−/−mice but were not influenced by TLR2 signaling. Intraperitoneal injection of anti–IL-17 monoclonal antibody (mAb), anti–IL-9 mAb, or recombinant mouse IL-4 accelerated the death ofTLR2−/−mice bearing MPE, and intraperitoneal injection anti–IL-17 mAb inTLR2−/−mice was associated with a significantly shorter survival time than in WT mice. We have demonstrated, for the first time, that TLR2 signaling promotes the development of MPE and accelerates the death of mice bearing MPE by directly suppressing Th17 cell differentiation and directly promoting Th2 cell differentiation, and also by indirectly suppressing Th9 cell differentiation via an IL-17–dependent mechanism.