The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

Friščić J, Böttcher M, Reinwald C, Bruns H, Wirth B, Popp S, Walker KI, Ackermann JA, Chen X, Turner J, Zhu H, Seyler L, Euler M, Kirchner P, Krüger R, Ekici AB, Major T, Aust O, Weidner D, Fischer A, Andes FT, Stanojevic Z, Trajkovic V, Herrmann M, Korb-Pap A, Wank I, Heß A, Winter J, Wixler V, Distler J, Steiner G, Kiener HP, Frey B, Kling L, Raza K, Frey S, Kleyer A, Bäuerle T, Hughes TR, Grüneboom A, Steffen U, Krönke G, Croft AP, Filer A, Köhl J, Klein K, Buckley CD, Schett G, Mougiakakos D, Hoffmann M (2021)

Publication Type: Journal article, Original article

Publication year: 2021

Journal

Immunity Elsevier

DOI: 10.1016/j.immuni.2021.03.003

Abstract

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

Authors with CRIS profile

Martin Böttcher Department of Medicine 5 – Haematology and Oncology Christiane Reinwald Department of Medicine 3 – Rheumatology and Immunology Heiko Bruns Department of Medicine 5 – Haematology and Oncology Benjamin Wirth Lehrstuhl für Innere Medizin III Sebastian Popp Lehrstuhl für Neurologie Xi Chen Professur für Translationale Immunologie Maximilien Euler Department of Medicine 3 – Rheumatology and Immunology René Krüger Institute of Human Genetics Arif Bülent Ekici Institute of Human Genetics Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology Isabel Wank Institut für Experimentelle und Klinische Pharmakologie und Toxikologie Andreas Heß Medizinische Fakultät Jörg Distler Professur für Molekulare Mechanismen der Organfibrose Benjamin Frey Department of Radiation Oncology Silke Frey Department of Medicine 3 – Rheumatology and Immunology Arnd Kleyer Department of Medicine 3 – Rheumatology and Immunology Tobias Bäuerle Professur für Multimodale Bildgebung in der präklinischen Forschung Ulrike Steffen Department of Medicine 3 – Rheumatology and Immunology Gerhard Krönke Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Markus Hoffmann Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

University of Birmingham GB United Kingdom (GB) Medizinische Universität Wien AT Austria (AT) Universität zu Lübeck DE Germany (DE) University of Belgrade / Универзитет у Београду RS Serbia (RS) Universitätsspital Zürich (USZ) CH Switzerland (CH) Universitätsklinikum Münster DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Cardiff University GB United Kingdom (GB)

How to cite

APA:

Friščić, J., Böttcher, M., Reinwald, C., Bruns, H., Wirth, B., Popp, S.,... Hoffmann, M. (2021). The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity. https://doi.org/10.1016/j.immuni.2021.03.003

MLA:

Friščić, Jasna, et al. "The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts." Immunity (2021).

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