IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation

Faas M, Ipseiz N, Ackermann J, Culemann S, Grüneboom A, Schröder F, Rothe T, Scholtysek C, Eberhardt M, Böttcher M, Kirchner P, Stoll C, Ekici AB, Fuchs M, Kunz M, Weigmann B, Wirtz S, Lang R, Hofmann J, Vera J, Vöhringer D, Michelucci A, Mougiakakos D, Uderhardt S, Schett G, Krönke G (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Immunity Elsevier

Book Volume: 54

Pages Range: 2531-2546.e5

Journal Issue: 11

DOI: 10.1016/j.immuni.2021.09.010

Abstract

Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.

Authors with CRIS profile

Maria Faas Professur für Immunologie Jochen Ackermann Department of Medicine 3 – Rheumatology and Immunology Fenja Schröder Professur für Modulation von Immunantworten Tobias Rothe Department of Medicine 3 – Rheumatology and Immunology Martin Eberhardt Lehrstuhl für Biochemie und Molekulare Medizin Martin Böttcher Department of Medicine 5 – Haematology and Oncology Arif Bülent Ekici Institute of Human Genetics Maximilian Fuchs Lehrstuhl für Medizinische Informatik Meik Kunz Lehrstuhl für Medizinische Informatik Benno Weigmann Medizinische Fakultät Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Roland Lang Professur für Angeborene Immunität und Pathogenerkennung Jörg Hofmann Lehrstuhl für Biochemie Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) David Vöhringer Department of Infection Biology Dimitrios Mougiakakos Medizinische Fakultät Stefan Uderhardt Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Gerhard Krönke Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

A086: Role of synovial macrophage subsets during inflammatory arthritis June 16, 2020 - June 15, 2023

Involved external institutions

Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS) DE Germany (DE) Luxembourg Institute of Health (CRP-Santé) LU Luxembourg (LU)

How to cite

APA:

Faas, M., Ipseiz, N., Ackermann, J., Culemann, S., Grüneboom, A., Schröder, F.,... Krönke, G. (2021). IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation. Immunity, 54(11), 2531-2546.e5. https://doi.org/10.1016/j.immuni.2021.09.010

MLA:

Faas, Maria, et al. "IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation." Immunity 54.11 (2021): 2531-2546.e5.

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