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.