دانلود رایگان مقاله انگلیسی تنظیم منفی اینتگرین CD11b سیگنال Mincle توسط مجموعه Lyn–SIRPα–SHP1 - نشریه NCBI 2018

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.

DISCUSSION

Mincle has a central role in the host defense against mycobacterial infection as the major receptor for mycobacterial cell wall component TDM. The activating role of this signaling molecule in the proinflammatory response has been well studied; however, little is known about the mechanism that leads to dampening of this inflammatory signal. In this study, we provide multiple lines of evidence demonstrating that CD11b is the crucial negative regulator of Mincle signaling and therefore has an important role in Mtb infection. First of all, our observation that CD11b deficiency resulted in a significantly enhanced Mincle-dependent inflammatory response against TDM and BCG challenge extends the function of CD11b in Mtb infection. Phagocytes from patients with tuberculosis possess augmented CD11b/CD18 expression, which is thought to promote cell adhesion and accumulation at the infection site.30 During Mtb infection, the immune response is mediated by TLRs, which are activated by various molecular patterns on Mtb.31 Recent work revealed that CD11b facilitates proteasomal degradation of Myd88 and TRIF upon TLR3, 4 and 9 activation, thereby inhibiting the inflammatory response.14 Bang and colleagues also reported that CD11b downregulates DC-mediated cross-priming through miR-146a.32 Here we demonstrated that CD11b interferes with the proinflammatory response induced by the Mtb-specific PAMP TDM and confirmed that live Mtb infection also induces increased cytokine production in CD11b− / − BMMs. Although TLR and Mincle signaling are negatively regulated by CD11b through different mechanisms, these signals converge on nuclear transcription factor-kappaB and synergistically enhance the inflammatory response toward Mtb infection.