National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
Nat Immunol. 2010 Aug;11(8):734-42. doi: 10.1038/ni.1908. Epub 2010 Jul 18.
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.
整合素对于炎症中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 αM（CD11b）与 Toll 样受体（TLR）触发的先天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败血症的影响。TLR 触发的磷脂酰肌醇 3-羟基激酶（PI(3)K）和效应蛋白 RapL 激活 CD11b，然后通过激活酪氨酸激酶Src 和 Syk 反馈抑制 TLR 信号。Syk 与 MyD88 和 TRIF 相互作用并诱导其酪氨酸磷酸化，导致这些衔接分子被 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 途径进行串扰，随后抑制先天免疫反应中的 TLR 信号。
