How psychological stress triggers arthritis flares via an IL-6-dependent pathway

Psychological stress has long been associated with worsening symptoms in rheumatoid arthritis (RA). However, the underlying mechanism connecting psychological stress to the occurrence of joint inflammation has remained poorly understood. In particular, how psychological stress can trigger inflammation in joints that were previously affected, even after the disease has gone into remission, remains an important unanswered question.

To answer this, a team of researchers from Chiba University, Japan, in collaboration with Asahi General Hospital, Japan, and International University of Health and Welfare Narita Hospital, Japan, investigated how psychological stress can reactivate arthritis. The study was led by Assistant Professor Shigeru Tanaka, along with Professor Hiroshi Nakajima from the Graduate School of Medicine, Chiba University. Their findings will be published in the journal Science Advances on October 16, 2026.

The researchers examined stress-induced arthritis flares in mice. They used a mouse model in which arthritis was allowed to enter a remission-like state before the animals were exposed to restraint stress. Following exposure to stress, they found that psychological stress reactivated inflammation in the joints. Using tissue analysis, immune-cell profiling, and molecular measurements, the researchers then traced the inflammatory signals activated by stress. The experiments revealed that stress activated the sympathetic nervous system and brown adipose tissues, a type of body fat involved in producing heat. This activation caused BAT to release interleukin-6 (IL-6), an inflammatory signaling protein.

“Our findings suggest that the effects of psychological stress on arthritis extend beyond the immune cells traditionally associated with autoimmune disease. Instead, stress can activate processes within other tissues that contribute to the return of joint inflammation,” explains Asst. Prof. Tanaka.

Furthermore, the researchers identified which cells within the joint respond to this circulating IL-6. Their findings pointed to fibroblast-like synoviocytes, specialized cells found in the synovial tissue surrounding the joints. IL-6 stimulates these cells to produce CXCL1, a chemokine (immune-signaling protein) that attracts neutrophils, a type of white blood cell involved in inflammation. The resulting recruitment of neutrophils contributes to the reactivation of joint inflammation. Blocking the CXCR2 receptor, which responds to CXCL1, significantly reduced stress-triggered arthritis in the mouse model.

The researchers further tested this pathway by blocking key receptors and monitoring changes in inflammatory markers, joint swelling, and immune-cell accumulation. When the mice were treated with a β3-adrenergic receptor antagonist, the researchers observed a reduction in plasma IL-6 levels, joint swelling, CXCL1 expression, and the accumulation of neutrophils in the joints. “Our findings suggest that targeting the stress-responsive pathways may offer a future therapeutic strategy that acts without broadly suppressing the immune system,” notes Prof. Nakajima.

Furthermore, the researchers examined whether this stress-related pathway was reflected in people with RA. They found that patients with Trp64Arg, a specific variant of the ADRB3 gene (which makes cells less responsive to stress-related hormones), showed a weaker link between perceived stress and arthritis activity when compared to patients without the variant. However, because this analysis was observational, the findings do not prove that stress directly caused changes in disease activity.

Overall, the findings suggest that arthritis may retain a form of tissue inflammatory memory that can be reactivated by stress independently of lymphocytes. This provides a biological explanation for how psychological stress can contribute to arthritis flares and identifies a stress-responsive pathway that could be explored as a potential therapeutic target. In the future, a better understanding of this pathway could help guide the development of strategies to improve disease management and the quality of life of people living with RA.

This article is based on a press release from Chiba University.