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.
Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome;
inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained
immunity.
Reference
Friščić, J., Böttcher, M., Reinwald, C., Bruns, H., Wirth, B., Popp, S. J., ... & Hoffmann, M. H. (2021). The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity, 54(5), 1002-1021.