A critical role for suppressor of cytokine signalling 3 in promoting M 1 macrophage activation and function in vitro and in vivo

Abstract

Summary Macrophages respond to their microenvironment and develop polarized functions critical for orchestrating appropriate inflammatory responses. Classical ( M 1) activation eliminates pathogens while alternative ( M 2) activation promotes regulation and repair. M1 macrophage activation is strongly associated with suppressor of cytokine signalling 3 ( SOCS 3) expression in vitro , but the functional consequences of this are unclear and the role of SOCS 3 in M 1‐macrophage polarization in vivo remains controversial. To address these questions, we defined the characteristics and function of SOCS 3‐expressing macrophages in vivo and identified potential mechanisms of SOCS 3 action. Macrophages infiltrating inflamed glomeruli in a model of acute nephritis show significant up‐regulation of SOCS 3 that co‐localizes with the M 1‐activation marker, inducible nitric oxide synthase. Numbers of SOCS 3 hi ‐expressing, but not SOCS 1 hi ‐expressing, macrophages correlate strongly with the severity of renal injury, supporting their inflammatory role in vivo . Adoptive transfer of SOCS 3‐short interfering RNA ‐silenced macrophages into a peritonitis model demonstrated the importance of SOCS 3 in driving production of pro‐inflammatory IL ‐6 and nitric oxide, while curtailing expression of anti‐inflammatory IL ‐10 and SOCS 1. SOCS 3‐induced pro‐inflammatory effects were due, at least in part, to its role in controlling activation and nuclear accumulation of nuclear factor‐κ B and activity of phosphatidylinositol 3‐kinase. We show for the first time that SOCS 3 also directs the functions of human monocyte‐derived macrophages, including efficient M 1‐induced cytokine production ( IL ‐1β, IL ‐6, IL ‐23, IL ‐12), attenuated signal transducer and activator of transcription 3 activity and ability of antigen‐loaded macrophages to drive T‐cell responses. Hence, M 1‐associated SOCS 3 was a positive regulator of pro‐inflammatory responses in our rodent models and up‐regulated SOCS 3 is essential for effective M 1‐macrophage activation and function in human macrophages.

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