Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Republic of Korea.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Exp Mol Med. 2018 Feb 5;50(2):e439. doi: 10.1038/emm.2017.256.
During mycobacteria infection, anti-inflammatory responses allow the host to avoid tissue damage caused by overactivation of the immune system; however, little is known about the negative modulators that specifically control mycobacteria-induced immune responses. Here we demonstrate that integrin CD11b is a critical negative regulator of mycobacteria cord factor-induced macrophage-inducible C-type lectin (Mincle) signaling. CD11b deficiency resulted in hyperinflammation following mycobacterial infection. Activation of Mincle by mycobacterial components turns on not only the Syk signaling pathway but also CD11b signaling and induces formation of a Mincle-CD11b signaling complex. The activated CD11b recruits Lyn, SIRPα and SHP1, which dephosphorylate Syk to inhibit Mincle-mediated inflammation. Furthermore, the Lyn activator MLR1023 effectively suppressed Mincle signaling, indicating the possibility of Lyn-mediated control of inflammatory responses. These results describe a new role for CD11b in fine-tuning the immune response against mycobacterium infection.
在分枝杆菌感染期间，抗炎反应使宿主能够避免免疫系统过度激活引起的组织损伤；然而，对于专门控制分枝杆菌诱导的免疫反应的负调节剂知之甚少。在这里，我们证明整合素 CD11b 是分枝杆菌 cord 因子诱导的巨噬细胞诱导型 C 型凝集素 (Mincle) 信号的关键负调节剂。CD11b 缺陷导致分枝杆菌感染后炎症过度。分枝杆菌成分激活 Mincle 不仅激活了 Syk 信号通路，还激活了 CD11b 信号通路，并诱导 Mincle-CD11b 信号复合物的形成。激活的 CD11b 募集 Lyn、SIRPα 和 SHP1，它们使 Syk 去磷酸化，从而抑制 Mincle 介导的炎症。此外，Lyn 激活剂 MLR1023 可有效抑制 Mincle 信号，表明 Lyn 介导的炎症反应控制的可能性。这些结果描述了 CD11b 在微调针对分枝杆菌感染的免疫反应中的新作用。
