Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b
Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b
复制标题
DOI：
10.1038/ni.1908
复制
发表时间：
2010-08-01
影响因子：
30.5
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Han, Chaofeng;Jin, Jing;Cao, Xuetao
整合素在炎症中对白细胞的迁移和功能至关重要。然而，在单核细胞和巨噬细胞中高表达的整合素α(M)(CD11b)与Toll样受体(TLR)触发的天然免疫之间的相互作用尚不清楚。在这里，我们报告CD11b缺陷增强了巨噬细胞中TLR介导的反应，使小鼠更容易受到内毒素休克和大肠杆菌引起的脓毒症的影响。CD11b被TLR触发的磷脂酰肌醇3-羟基激酶(PI(3)K)和效应子RAPL激活，并通过激活酪氨酸激酶Src和Syk反馈抑制TLR信号转导。SYK与MyD88和TRIF相互作用并诱导其酪氨酸磷酸化，从而导致这些接头分子被E3泛素连接酶Cbl-b降解。因此，TLR触发的活性CD11b整合素与MyD88和TRIF通路发生串扰，随后在先天性免疫反应中抑制TLR信号转导。
Integrins are critical for the migration and function of leukocytes in inflammation. However, the interaction between integrin alpha(M) (CD11b), which has high expression in monocytes and macrophages, and Toll-like receptor (TLR)-triggered innate immunity remains unclear. Here we report that CD11b deficiency enhanced TLR-mediated responses in macrophages, rendering mice more susceptible to endotoxin shock and Escherichia coli-caused sepsis. CD11b was activated by TLR-triggered phosphatidylinositol 3-OH kinase (PI(3) K) and the effector RapL and fed back to inhibit TLR signaling by activating the tyrosine kinases Src and Syk. Syk interacted with and induced tyrosine phosphorylation of MyD88 and TRIF, which led to degradation of these adaptor molecules by the E3 ubiquitin ligase Cbl-b. Thus, TLR-triggered, active CD11b integrin engages in crosstalk with the MyD88 and TRIF pathways and subsequently inhibits TLR signaling in innate immune responses.