Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function

Journal of Leukocyte Biology

Eileen T. Bishop²  Heather M. Wilson²  Robert N. Barker²  Judith E. Allen¹  Claire S. Whyte²  Dominik Rückerl¹  Silvia Gaspar-Pereira²  Andrew J. Rees and³ 

[1]  Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom;Division of Applied Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom;Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria Division of Applied Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom;

关键词: inflammation;    M1 activation;    M2 activation;    inducible nitric oxide synthase;    arginase I;    Brugia malayi;   

DOI  :  10.1189/jlb.1110644

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Macrophages become activated by their environment and develop polarized functions: classically activated (M1) macrophages eliminate pathogens but can cause tissue injury, whereas alternatively activated (M2) macrophages promote healing and repair. Mechanisms directing polarized activation, especially in vivo, are not understood completely, and here, we examined the role of SOCS proteins. M2 macrophages activated in vitro or elicited by implanting mice i.p. with the parasitic nematode Brugia malayi display a selective and IL-4-dependent up-regulation of SOCS1 but not SOCS3. Using siRNA-targeted knockdown in BMDM, we reveal that the enhanced SOCS1 is crucial for IL-4-induced M2 characteristics, including a high arginase I:iNOS activity ratio, suppression of T cell proliferation, attenuated responses to IFN-γ/LPS, and curtailed SOCS3 expression. Importantly, SOCS1 was essential in sustaining the enhanced PI3K activity that drives M2 activation, defining a new regulatory mechanism by which SOCS1 controls M2 polarization. By contrast, for M1 macrophages, SOCS1 was not only an important regulator of proinflammatory mediators (IL-6, IL-12, MHC class II, NO), but critically, for M1, we show that SOCS1 also restricted IL-10 secretion and arginase I activity, which otherwise would limit the efficiency of M1 macrophage proinflammatory responses. Together, our results uncover SOCS1, not only as a feedback inhibitor of inflammation but also as a critical molecular switch that tunes key signaling pathways to effectively program different sides of the macrophage balance.

【 授权许可】

Unknown