Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

Nitric oxide (NO) produced by macrophages (Ms) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. M arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in Ms. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated Ms. We found that mycobacteria-infected Ms produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected Ms

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