The balance between pro-inflammatory and anti-inflammatory macrophage generation, a process known as polarization, is critical for immune homoeostasis. Identifying the molecular mechanisms underlying polarization and the generation of anti-inflammatory macrophages is an area of high current interest. Our previous work has demonstrated that integrin CD11b promotes IL-10 production in macrophages by activating the Sarcoma gene (Src), yet whether and how Src modulates anti-inflammatory macrophages is not known. Here we show that Src inhibitor (Dasatinib)-treated mice were highly susceptible to dextran sulfate sodium (DSS)-induced colitis, with a much more sever inflammation response, accompanying by high TNF-α, and low IL-10 expression. Inhibition of Src enhanced the expression of pro-inflammatory macrophage marker inducible nitric oxide synthase (iNOS), but reduced the expression of anti-inflammatory macrophage marker arginase1 (Arg1) in both intestinal macrophages and bone marrow-derived macrophages (BMDMs). Overexpression of constitutively activated Src promoted IL-4-induced expression of Arg1 through STAT6 phosphorylation, and Jak1 was also involved in this process. Our results reveal that the IL-4-Src-STAT6 pathway plays a major role in polarizing anti-inflammatory macrophage generation and suggest a potential anti-inflammatory role for Src in inflammatory diseases.
Keywords: Inflammation; Macrophage polarization; STAT6; Src.
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