Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b

Abstract

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.

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

“…CD11b is widely expressed in DCs, NK cells, macrophages, and activated CTLs. Our study showed that CD11b on macrophages could be activated by the TLR4 signal via TLRtriggered PI3K and the effector RapL, and feedback negatively inhibited TLR4 signaling (15). In addition, CD11b expression also increases rapidly in NK cells upon TLR3 ligand stimulation, and, in turn, negatively regulates NK cell activation (16).…”

“…CD11b-deficient mice (B6.129S4-Itgam tm1Myd /J; 003991) and OT-I mice (C57BL/6-Tg(TcraTcrb)1100Mjb/ J;003831) were described previously (8,15,16). All animal experiments were undertaken in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, with the approval of the Scientific Investigation Board of the Second Military Medical University.…”

“…CD11b is extensively expressed in most immune cells, such as DCs, monocytes/macrophages, granulocytes, and NK cells, and it participates in cell activation, chemotaxis, cytotoxicity, and phagocytosis (13,14). Our previous reports showed that CD11b is able to maintain immunological tolerance and inhibit inflammatory responses by repressing TLR3 signaling in NK cells and TLR4 signaling in macrophages (15,16). Analogously, CD11b, abundantly expressed in DCs, can inhibit DC-primed CD4 + T cell activation and promote peripheral tolerance by breaking Th17 differentiation (17,18).…”

The Calcineurin B Subunit (CnB) Is a New Ligand of Integrin αM That Mediates CnB-Induced Apo2L/TRAIL Expression in Macrophages

“…In contrast, integrin aMb 2 is crucial for effective FcR-mediated immunity to melanoma (53) and promotes the survival of mouse NK cells (54). In addition, it inhibits TLR-triggered inflammatory responses and prevents excessive production of proinflammatory cytokines and type I IFN (55). Recent research has highlighted a critical role for inflammation in the development of cancers, based on the observation that innate immune cells drive tumor progression by producing proinflammatory factors such as TNF-a and IL-6 (56-58).…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…), Nodlike family proteins (NLRX1, NLRC5, 18,19 etc. ), membrane molecules (CD300F, CD11b, PECAM-1, 20,21 etc. ), endosome/lysosome-localized molecules (Rab7b, 22,23 CLM-3 24 ), gene transcription coactivators (beta-catenin 25 ), antigen-presenting molecules (MHC I and MHC II 26,27 ), and even HSP70, 28 HSP70L1 29 and NGF.…”