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

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: 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 Fischer, Fabian 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
• Journal: Immunity (Immunity) Vol. 54 Issue 5 Pg. 1002-1021.e10 (05 11 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 33761330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Inflammation Mediators
• Complement System Proteins

Topics

• Adaptive Immunity (immunology)
• Animals
• Arthritis, Rheumatoid (immunology)
• Cell Line
• Complement System Proteins (immunology)
• Dogs
• Fibroblasts (immunology)
• Humans
• Inflammation (immunology)
• Inflammation Mediators (immunology)
• Madin Darby Canine Kidney Cells
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Rats, Wistar
• Signal Transduction (immunology)
• Synovial Membrane (immunology)
• Rats