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.
Bibliographical noteFunding Information:
We thank the Consortium for Functional Glycomics and the Laboratory Animal Research Center at Yonsei University. This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (grant number: NRF-2012M3A9B4028272); Collaborative Genome Program for Fostering New Post-Genome industry through the National Research Foundation of Korea (NRF) funded by the Ministry of Science ICT and Future Planning (grant number: 2016M3C9A4 921712); and Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning (grant number: NRF-2016R1A6A3A11934835).
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry