WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury.
WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury.
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WISP1-α v beta 3 整合素信号传导正向调节脓毒症引起的肺损伤中 TLR 触发的炎症反应
DOI：
10.1038/srep28841
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发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Chen Z;Ding X;Jin S;Pitt B;Zhang L;Billiar T;Li Q
我们最近注意到，基质细胞蛋白WISP 1通过整合素β6导致脓毒症诱导的急性肺损伤（ALI）。在本研究中，我们进一步研究了WISP 1对脓毒症后小鼠肺中TLR信号传导的调节以及TLR 4介导的巨噬细胞中TNF-α的释放。在证实TLR 4和CD 14在脓毒症介导的ALI中起关键作用后，我们现在证明肺内αvβ3以TLR 4、CD 14依赖的方式在多微菌脓毒症中增加。比较培养的巨噬细胞显示，WISP 1增加了具有αvβ3基线表达的RAW264.7细胞的TNF-α释放，但腹膜巨噬细胞（PMMC）的原代培养物需要激活TLR 4以诱导αvβ3的从头合成，从而使WISP 1能够刺激TNF-α的释放。当从β3−/−小鼠中分离的PMS 1中WISP 1的作用丧失时，对β3整联蛋白的特异性需求是明显的。WISP 1增强TLR 4介导的ERK信号通路，ERK抑制剂U 0126阻断LPS诱导的β3整合素表达，WISP 1增强TNF-α释放。总之，这些数据表明，WISP 1-αvβ3整合素信号转导参与巨噬细胞中的TLR 4途径，并且可能是脓毒症诱导的肺损伤中TLR 4/CD 14介导的炎症的重要贡献者。
We recently noted that the matricellular protein WISP1 contributes to sepsis induced acute lung injury (ALI) via integrin β6. In the current study, we pursued further aspects of WISP1 modulation of TLR signaling in lungs of mice after sepsis and TLR4 mediated release of TNF-α in macrophages. After confirming that TLR4 and CD14 are critical in transducing sepsis mediated ALI, we now demonstrate that intrapulmonary αvβ3 is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion. Comparison of cultured macrophages revealed that WISP1 increased release of TNF-α from RAW264.7 cells with baseline expression of αvβ3, but primary cultures of peritoneal macrophages (PMø) required activation of TLR4 to induce de novo synthesis of αvβ3 enabling WISP1 to stimulate release of TNF-α. The specific requirement for β3 integrin was apparent when the effect of WISP1 was lost in PMø isolated from β3−/− mice. WISP1 enhanced TLR4 mediated ERK signaling and U0126 (an ERK inhibitor) blocked LPS induced β3 integrin expression and WISP1 enhanced TNF-α release. Collectively these data suggest that WISP1-αvβ3 integrin signaling is involved in TLR4 pathways in macrophages and may be an important contributor to TLR4/CD14 mediated inflammation in sepsis induced lung injury.