Suppressor of cytokine signaling 3 in macrophages prevents exacerbated Interleukin-6-Dependent Arginase-1 activity and early permissiveness to experimental tuberculosis

Erik Schmok, Mahin Abad Dar, Jochen Behrends, Hanna Erdmann, Dominik Rückerl, Tanja Endermann, Lisa Heitmann, Manuela Hessmann, Akihiko Yoshimura, Stefan Rose-John, Jürgen Scheller, Ulrich Emil Schaible, Stefan Ehlers, Roland Lang, Christoph Hölscher

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 in Mycobacterium 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/loxP mice resulted in remarkably higher bacterial loads in infected lungs and exacerbated pulmonary inflammation. This increased susceptibility to Mtb infection 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/loxP mice appears to favor the initial replication of Mtb particularly in Arg1-positive cells. Neutralization of IL-6 in Mtb-infected LysMcreSOCS3loxP/loxP mice reduced arginase activity and restored control of mycobacterial replication in LysMcreSOCS3loxP/loxP mice. Our data reveal an unexpected role of SOCS3 during experimental TB: macrophage SOCS3 restrains early expression of Arg1 and helps limit Mtb replication in resident lung macrophages, thereby limiting the growth of mycobacteria. Together, SOCS3 keeps IL-6-dependent divergent macrophage responses such as Nos2 and Arg1 expression under control and safeguard protective macrophage effector mechanisms.

Original languageEnglish
Article number1537
JournalFrontiers in Immunology
Volume8
Issue numberNOV
DOIs
Publication statusPublished - 2017 Nov 10

Fingerprint

Permissiveness
Arginase
Interleukin-6
Tuberculosis
Macrophages
Cytokines
Mycobacterium tuberculosis
Macrophage Activation
Mycobacterium Infections
Lung
Bacterial Load
Mycobacterium
Aerosols
Nitric Oxide Synthase
Pneumonia

Keywords

  • Arginase I
  • Knockout
  • Macrophages
  • Mice
  • Mycobacterium tuberculosis
  • Suppressor of cytokine signaling proteins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Suppressor of cytokine signaling 3 in macrophages prevents exacerbated Interleukin-6-Dependent Arginase-1 activity and early permissiveness to experimental tuberculosis. / Schmok, Erik; Dar, Mahin Abad; Behrends, Jochen; Erdmann, Hanna; Rückerl, Dominik; Endermann, Tanja; Heitmann, Lisa; Hessmann, Manuela; Yoshimura, Akihiko; Rose-John, Stefan; Scheller, Jürgen; Schaible, Ulrich Emil; Ehlers, Stefan; Lang, Roland; Hölscher, Christoph.

In: Frontiers in Immunology, Vol. 8, No. NOV, 1537, 10.11.2017.

Research output: Contribution to journalArticle

Schmok, E, Dar, MA, Behrends, J, Erdmann, H, Rückerl, D, Endermann, T, Heitmann, L, Hessmann, M, Yoshimura, A, Rose-John, S, Scheller, J, Schaible, UE, Ehlers, S, Lang, R & Hölscher, 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, vol. 8, no. NOV, 1537. https://doi.org/10.3389/fimmu.2017.01537
Schmok, Erik ; Dar, Mahin Abad ; Behrends, Jochen ; Erdmann, Hanna ; Rückerl, Dominik ; Endermann, Tanja ; Heitmann, Lisa ; Hessmann, Manuela ; Yoshimura, Akihiko ; Rose-John, Stefan ; Scheller, Jürgen ; Schaible, Ulrich Emil ; Ehlers, Stefan ; Lang, Roland ; Hölscher, Christoph. / Suppressor of cytokine signaling 3 in macrophages prevents exacerbated Interleukin-6-Dependent Arginase-1 activity and early permissiveness to experimental tuberculosis. In: Frontiers in Immunology. 2017 ; Vol. 8, No. NOV.
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AU - Rose-John, Stefan

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