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Abstract
Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11bhi regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam−/−) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses.
Highlights
Interleukin-10 (IL-10) is an anti-inflammatory cytokine with a crucial role in preventing inflammatory and autoimmune pathologies functioning at different stages of an immune response and possibly at different anatomical locations via signal transducer and activator of transcription 3 (STAT3)[1,2]
It is well known that the TNF-αplays a central role in inflammatory bowel disease (IBD) pathology and anti-TNF-αtherapy has been shown to be efficacious in the treatment of ulcerative colitis and Crohn’s disease[11]
We previously reported that regulatory dendritic cells with high expression of CD11b produced more IL-10 than common DCs, and CD11b negatively regulated TLRs-induced signals and responses in macrophages during acute inflammation[28,29]
Summary
Interleukin-10 (IL-10) is an anti-inflammatory cytokine with a crucial role in preventing inflammatory and autoimmune pathologies functioning at different stages of an immune response and possibly at different anatomical locations via signal transducer and activator of transcription 3 (STAT3)[1,2]. Our previous studies show that stromal microenvironment of spleen, liver, lung can drive generation of a new population of CD11bhi regulatory DCs with higher IL-10 production These regulatory DCs could down-regulate T cell response, maintaining tolerance and attenuating T cell-mediated airway inflammation and hepatitis[25,26,27,28]. Following our preliminary observation that CD11b-deficient mice are more susceptible to DSS-induced colitis, in this study, we uncovered the polarizing role and the underlying mechanisms of CD11b in promoting TLR-triggered IL-10 production in macrophages and DCs. We demonstrated that CD11b increased Src activation, which resulted in decreased NF-κB and increased AP-1 activation. Our results outline a new homeostatic regulation of TLR-induced pro-inflammatory and anti-inflammatory responses by integrin-activated Src-Akt signal axis
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