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

Research output: Contribution to journalArticlepeer-review


  • Jasna Friščić
  • Martin Böttcher
  • Christiane Reinwald
  • Heiko Bruns
  • Benjamin Writh
  • Samantha-Josefine Popp
  • Kellie Irene Walker
  • Jochen A. Ackermann
  • Xi Chen
  • 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 Hermann
  • Adelheid Korb-Pap
  • Isabel Wank
  • Andreas Hess
  • Jonathan Winter
  • Viktor Wixler
  • Jörg Distler
  • Günter Steiner
  • Hans P. Kiener
  • Benjamin Frey
  • Lasse Kling
  • Silke Frey
  • Arnd Kleyer
  • Tobias Bäuerle
  • Anika Grüneboom
  • Ulrike Steffen
  • Gerhard Krönke
  • Jörg Köhl
  • Kerstin Klein
  • Georg Schett
  • Dimitrious Mougiakakos
  • Markus H. Hoffmann

Colleges, School and Institutes


Here, we define the molecular and cellular mechanism of inflammation-mediated tissue priming that determines recurrence of arthritis at specific predilection sites. Re-exposure of joints to inflammatory stimuli caused prolonged and aggravated clinical signs of experimental arthritis as well as higher levels of inflammation and tissue damage. Tissue priming developed locally and was independent of the adaptive immune system, but progressively spread to contralateral joints. Fibroblasts isolated from paws repeatedly exposed to inflammatory stimuli (“primed fibroblasts”) exhibited enhanced metabolic activity and NLRP3 inflammasome activation leading to functional changes with higher migration, invasiveness and osteoclastogenic potential. Human fibroblasts derived from established arthritis exhibited a similar primed functional phenotype as compared to fibroblasts from very early arthritis or non-inflamed joints. Transcriptomic and epigenomic analyses revealed upregulation of the complement system and confirmed metabolic reprogramming in primed fibroblasts. Genetic and pharmacological targeting of members of a complement C3 – C3a receptor – mTOR/HIF1α – NLRP3 axis reversed the primed fibroblast phenotype, induced a pro-resolving senescet phenotype and abrogated inflammatory tissue priming in vitro and in vivo. Our results suggest that inflammatory tissue priming is a process that leads to intracellular complement C3/C3aR activation and mTOR/HIF-1αmediated metabolic activation of fibroblasts that trigger enhanced NLRP3 inflammasome activity and in consequence facilitate recurrence of inflammation.

Bibliographic note

Acknowledgements: This work was supported by the DFG (FG 2886–TP04 to U.S., TP08 to D.M. and M.H.H., Z-project [A.K.]; CRC1181-B03 to M.H.H., A05 to S.F., and Z2 to T.B.; EXC2167 PMI, TI-3 to J.K.), the European Union (ERC Synergy grant 810316 4DnanoSCOPE to G.S.), the EU/EFPIA IMI 2 RTCure (77735). X.C. was supported by the Chinese Scholarship Council. We thank the Optical imaging center Erlangen and the Precinical imaging platform Erlangen. We further thank U. Appelt, M. Mroz, H. Danzer, D. Beckmann, K. von Dalwigk, A. Rauschenberg and L. Möller for technical assistance, F. Hartmann for collation of patient characteristics, and M. Göksu for recruitment of human synovial tissue. We also thank G. Kollias, BSRC Alexander Fleming, for sharing Col6a1-cre mice. The graphical abstract was created by Sundary Sormendi using


Original languageEnglish
Pages (from-to)1-31
Issue number00
Early online date23 Mar 2021
Publication statusE-pub ahead of print - 23 Mar 2021


  • arthritis, synovial fibroblasts, tissue priming, complement system, cell metabolism, cellular senescence, inflammation, inflammasome, trained immunity, mechanistic target of rapamycin