Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis

Schmok E, Dar MA, Behrends J, Erdmann H, Rueckerl D, Endermann T, Heitmann L, Hessmann M, Yoshimura A, Rose-John S, Scheller J, Schaible UE, Ehlers S, Lang R, Hoelscher C (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Frontiers in Immunology Frontiers Research Foundation / Frontiers Media

Book Volume: 8

DOI: 10.3389/fimmu.2017.01537

Abstract

Suppressor of cytokine signaling 3 (SOCS3) is a feedback inhibitor of interleukin (IL)-6 signaling in macrophages. In the absence of this molecule, macrophages become extremely prone to an IL-6-dependent expression of arginase-1 (Arg1) and nitric oxide synthase (NOS)2, the prototype markers for alternative or classical macrophage activation, respectively. Because both enzymes are antipodean macrophage effector molecules inMycobacterium tuberculosis(Mtb) infection, we assessed the relevance of SOCS3 for macrophage activation during experimental tuberculosis using macrophage-specific SOCS3-deficient (LysMcreSOCS3loxP/loxP) mice. Aerosol infection of LysMcreSOCS3loxP/loxPmice resulted in remarkably higher bacterial loads in infected lungs and exacerbated pulmonary inflammation. This increased susceptibility toMtbinfection was accompanied by enhanced levels of both classical and alternative macrophage activation. However, high Arg1 expression preceded the increased induction of NOS2 and at early time points of infection mycobacteria were mostly found in cells positive for Arg1. This sequential activation of Arg1 and NOS2 expression in LysMcreSOCS3loxP/loxPmice appears to favor the initial replication ofMtbparticularly in Arg1-positive cells. Neutralization of IL-6 inMtb-infected LysMcreSOCS3loxP/loxPmice reduced arginase activity and restored control of mycobacterial replication in LysMcreSOCS3loxP/loxPmice. Our data reveal an unexpected role of SOCS3 during experimental TB: macrophage SOCS3 restrains early expression of Arg1 and helps limitMtbreplication in resident lung macrophages, thereby limiting the growth of mycobacteria. Together, SOCS3 keeps IL-6-dependent divergent macrophage responses such asNos2andArg1expression under control and safeguard protective macrophage effector mechanisms.

Authors with CRIS profile

Roland Lang Professur für Angeborene Immunität und Pathogenerkennung

Involved external institutions

Forschungszentrum Borstel - Leibniz-Zentrum für Medizin und Biowissenschaften / Research Center Borstel - Leibniz-Center for Medicine and Biosciences DE Germany (DE) Keio University / 慶應義塾大学 JP Japan (JP) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE)

How to cite

APA:

Schmok, E., Dar, M.A., Behrends, J., Erdmann, H., Rueckerl, D., Endermann, T.,... Hoelscher, C. (2017). Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.01537

MLA:

Schmok, Erik, et al. "Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis." Frontiers in Immunology 8 (2017).

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