Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock.
Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock.
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DOI：
10.1016/j.immuni.2016.05.005
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发表时间：
2016-06-21
期刊：
影响因子：
32.4
通讯作者：
Coligan JE
中科院分区：
文献类型：
--
作者：
Voss OH;Murakami Y;Pena MY;Lee HN;Tian L;Margulies DH;Street JM;Yuen PS;Qi CF;Krzewski K;Coligan JE
受体 CD300b 通过未知机制参与调节对细菌感染的免疫反应。在这里，我们将 CD300b 鉴定为脂多糖 (LPS) 结合受体，并确定了 CD300b 增强感染性休克的机制。体内耗竭和过继转移研究确定表达 CD300b 的巨噬细胞是加剧脓毒症的关键细胞类型。我们发现 CD300b 及其适配器 DAP12 在 LPS 结合后与 Toll 样受体 4 (TLR4) 相关，从而增强 TLR4 适配器 MyD88 和 TRIF 依赖性信号传导，导致促炎细胞因子风暴升高。 CD300b-TLR4 复合物的 LPS 参与导致脾酪氨酸激酶 (Syk) 和磷脂酰肌醇-4,5-二磷酸 3-激酶 (PI3K) 的募集和激活。这导致 ERK1/2 蛋白激酶和 NFκB 转录因子介导的信号通路受到抑制，从而导致白细胞介素 10 (IL-10) 的产生减少。总的来说，我们的数据描述了骨髓细胞中 CD300b 响应 LPS 调节 TLR4 信号传导的机制。
Receptor CD300b is implicated in regulating the immune response to bacterial infection by an unknown mechanism. Here, we identified CD300b as an lipopolysaccharide (LPS)-binding receptor and determined the mechanism underlying CD300b augmentation of septic shock. In vivo depletion and adoptive transfer studies identified CD300b-expressing macrophages as the key cell type augmenting sepsis. We showed that CD300b, and its adaptor DAP12, associated with Toll-like receptor 4 (TLR4) upon LPS binding, thereby enhancing TLR4-adaptor MyD88- and TRIF-dependent signaling that resulted in an elevated pro-inflammatory cytokine storm. LPS engagement of the CD300b-TLR4 complex led to the recruitment and activation of spleen tyrosine kinase (Syk) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). This resulted in an inhibition of the ERK1/2 protein kinase- and NFκB transcription factor-mediated signaling pathways, which subsequently led to a reduced interleukin 10 (IL-10) production. Collectively, our data describe a mechanism of TLR4 signaling regulated by CD300b in myeloid cells in response to LPS.