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

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

*Corresponding author for this work
5 Citations (Scopus)


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.

Original languageEnglish
Issue number5
Pages (from-to)1002-1021.e10
Publication statusPublished - 11.05.2021

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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