Psychological Stress Triggers Arthritis Flares in Mice via 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. Headed by a team at Chiba University, a study in mice suggests that arthritis may retain a form of tissue inflammatory memory that can be reactivated by stress.

The study results offer up a biological explanation for how psychological stress can contribute to arthritis flares, and identify a stress-responsive pathway that could be explored as a potential therapeutic target. Better understanding of this pathway in the future could help guide the development of strategies to improve disease management and the quality of life of people living with RA.

“Our findings suggest that targeting the stress-responsive pathways may offer a future therapeutic strategy that acts without broadly suppressing the immune system,” noted research co-lead professor Hiroshi Nakajima, MD, PhD, at the Graduate school of Medicine. Nakajima is senior and co-corresponding author of the researchers’ published paper in Science Advances , titled “ Fibroblast-like synoviocytes exacerbate autoimmune arthritis upon psychological stress in an IL-6–dependent manner .” Psychological stress affects a variety of biological processes, including the immune system, the authors wrote.

“It is well documented that acute psychological stress exacerbates inflammatory diseases.” However, while psychological stress can exacerbate autoimmune diseases such as rheumatoid arthritis (RA), the underlying biological mechanisms aren’t aren’t well understood. “The relationship between psychological stress and the exacerbation of RA has been recognized over the past few decades, but the underlying molecular mechanisms have remained unclear,” the team continued.

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. “... the mechanisms underlying tissue inflammation during remission remain unclear,” they noted.

To answer this, the Chiba University team, in collaboration with researchers at Asahi General Hospital, and International University of Health and Welfare Narita Hospital, investigated how psychological stress can reactivate arthritis, examining stress-induced flares in a mouse model.

For their study the researchers used an antigen-induced arthritis (AIA) mouse model in which arthritis was allowed to enter a remission-like state before the animals were exposed to restraint stress. Their experiments indicated that exposure psychological stress reactivated inflammation in the joints.

Using tissue analysis, immune-cell profiling and molecular measurements, the researchers traced the inflammatory signals activated by stress, finding that stress activated the sympathetic nervous system and brown adipose tissues (BAT), a type of body fat involved in producing heat.

Stress 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,” said study co-lead assistant professor Shigeru Tanaka, at Chiba University Graduate School of Medicine.

The researchers further identified which cells within the joint respond to this circulating IL-6. Their findings pointed to fibroblast-like synoviocytes (FLS), 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. “In the RA joint, various cells, including macrophages and FLS, produce IL-6, creating an inflammatory network through their interactions,” the investigators explained.

“Our study demonstrated a phenomenon in which IL-6 originates from outside the joint and stimulates FLS, leading to the recurrence of arthritis.” The researchers further tested the 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 current research revealed that β3-adrenergic receptor blockade successfully suppresses stress-induced arthritis flares,” they wrote.

“This finding suggests a possible therapeutic strategy targeting the sympathetic nervous system.” Nakajima added, “Our findings suggest that targeting the stress-responsive pathways may offer a future therapeutic strategy that acts without broadly suppressing the immune system.” The researchers in addition 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. “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,” the team concluded.