Fibroblast-like synoviocytes exacerbate autoimmune arthritis upon psychological stress in an IL-6-dependent manner

Psychological stress affects the immune system and exacerbates autoimmune diseases such as rheumatoid arthritis (RA), but the mechanisms underlying tissue inflammation during remission remain unclear. Here, we show that tube restraint stress exacerbates joint inflammation in a murine arthritis model during remission. This exacerbation required interleukin-6 (IL-6) produced by brown adipose tissue (BAT) following sympathetic activation. Fibroblast-like synoviocytes expressing the IL-6 receptor subunit gp130 were critical mediators, as IL-6 stimulated these cells to produce the neutrophil chemoattractant CXCL1. Pharmacological blockade of the β3-adrenergic receptor significantly attenuated stress-induced arthritis flares. In patients with RA, carriers of the hypofunctional Trp64Arg variant of ADRB3 showed no positive correlation between psychological stress and disease activity, whereas noncarriers did. These findings identify a BAT-IL-6-fibroblast axis that reactivates inflammatory memory in arthritis and suggest that targeting stress-responsive pathways may provide a complementary therapeutic strategy alongside current RA treatments without broadly suppressing systemic immunity.