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

Publication

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

Journal Paper/Review - Mar 23, 2021

Friščić Jasna, Böttcher Martin, Reinwald Christiane, Bruns Heiko, Wirth Benjamin, Popp Samantha-Josefine, Walker Kellie Irene, Ackermann Jochen A, Chen Xiang, Turner Jason, Zhu Honglin, Seyler Lisa, Euler Maximilien, Kirchner Philipp, Krüger René, Ekici Arif B, Major Triin, Aust Oliver, Weidner Daniela, Fischer Anita, Andes Fabian T, Stanojevic Zeljka, Trajkovic Vladimir, Herrmann Martin, Korb-Pap Adelheid, Wank Isabel, Hess Andreas, Winter Johnathan, Wixler Viktor, Distler Jörg, Steiner Günter, Kiener Hans P, Frey Benjamin, Kling Lasse, Raza Karim, Frey Silke, Kleyer Arnd, Bäuerle Tobias, Hughes Timothy R, Grüneboom Anika, Steffen Ulrike, Krönke Gerhard, Croft Adam P, Filer Andrew, Köhl Jörg, Klein Kerstin, Buckley Christopher D, Schett Georg, Mougiakakos Dimitrios, Hoffmann Markus H

Citation

Friščić J, Böttcher M, Reinwald C, Bruns H, Wirth B, Popp S, Walker K, Ackermann J, Chen X, Turner J, Zhu H, Seyler L, Euler M, Kirchner P, Krüger R, Ekici A, Major T, Aust O, Weidner D, Fischer A, Andes F, Stanojevic Z, Trajkovic V, Herrmann M, Korb-Pap A, Wank I, Hess A, Winter J, Wixler V, Distler J, Steiner G, Kiener H, Frey B, Kling L, Raza K, Frey S, Kleyer A, Bäuerle T, Hughes T, Grüneboom A, Steffen U, Krönke G, Croft A, Filer A, Köhl J, Klein K, Buckley C, Schett G, Mougiakakos D, Hoffmann M. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 2021; 54:1002-1021.e10.

Type

Journal Paper/Review (English)

Journal

Immunity 2021; 54

Publication Date

Mar 23, 2021

Issn Electronic

1097-4180

Pages

1002-1021.e10

Brief description/objective

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.