Abstract
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.
Highlights
The hallmark of Mycobacterium tuberculosis (Mtb) infection is the formation of a granuloma, a compact aggregate of immune cells.[1]
Increased cytokine production against mycobacteria in CD11b-deficient mice To examine the involvement of the integrin receptor in antimycobacterial infection, Bone marrow-derived macrophages (BMMs) from WT, CD11b-deficient (CD11b − / −) and macrophage-inducible C-type lectin (Mincle)-deficient (Mincle− / −) mice were challenged with Bacillus Calmette-Guérin (BCG)
All BMMs tested exhibited comparable phagocytic ability, even in the presence of TDM-coated particles (Supplementary Figure 1). These results indicate that CD11b deficiency may affect anti-mycobacterial cytokine production, which is not related to phagocytosis
Summary
The hallmark of Mycobacterium tuberculosis (Mtb) infection is the formation of a granuloma, a compact aggregate of immune cells.[1] The granuloma has been thought to function as a host defense mechanism to prevent further spread of Mtb; recent studies suggest that the granuloma can shelter the bacteria and ensure persistence of these organisms in a latent form.[2,3] clearance of the mycobacteria that persist in the granuloma is required for efficient clearance of the infection. Understanding the protective mechanism of negative regulators of granuloma formation will elucidate key targets for the development of immune therapies to fight Mtb infection
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