Sympathetic Activation and Fibroblast-Like Synoviocytes Drive Stress-Triggered Joint Inflammation

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Summary of  Science Advances https://doi.org/10.1126/sciadv.aec9257
Dr. Jun Tamura et al.

Points

Researchers from Chiba University investigated the biological mechanisms connecting psychological stress to the reactivation of joint inflammation during rheumatoid arthritis remission using murine models.
Experimental restraint stress activated the sympathetic nervous system and brown adipose tissue causing the release of interleukin-6 into the systemic circulation.
Circulating interleukin-6 stimulated fibroblast like synoviocytes expressing gp130 to produce the chemokine CXCL1 which subsequently recruited inflammatory neutrophils into the joint tissue.
Pharmacological antagonism of the beta3 adrenergic receptor significantly attenuated plasma interleukin-6 levels joint swelling CXCL1 expression and neutrophil accumulation in the murine models.
Human observational data confirmed that rheumatoid arthritis patients carrying the hypofunctional Trp64Arg variant of ADRB3 lacked the stress disease activity correlation seen in noncarriers.

Summary

This study evaluated the mechanistic pathway by which psychological stress reactivates joint inflammation during rheumatoid arthritis (RA) remission. Published in Science Advances by researchers from Chiba University, Asahi General Hospital, and International University of Health and Welfare Narita Hospital, the investigation addressed the longstanding clinical observation that psychological stress exacerbates autoimmune symptoms. Given that the precise biological links between stress and the reactivation of previously inflamed joints remained poorly understood, the research sought to determine whether neuroendocrine signaling and non-lymphoid tissues contribute to stress-induced arthritis flares.

Using a murine model of antigen-induced arthritis allowed to enter clinical remission, researchers exposed the mice to tube restraint stress. The experiments revealed that psychological stress activated the sympathetic nervous system and brown adipose tissue (BAT), inducing the secretion of interleukin-6 (IL-6). Circulating IL-6 targeted gp130-expressing fibroblast-like synoviocytes within the synovial tissue, stimulating them to produce the neutrophil chemoattractant CXCL1, which recruited neutrophils and drove joint inflammation. Pharmacological blockade of the beta3-adrenergic receptor effectively attenuated plasma IL-6 levels, CXCL1 expression, neutrophil accumulation, and joint swelling. Furthermore, observational analysis in human RA patients carrying the hypofunctional Trp64Arg variant of the ADRB3 gene revealed no positive correlation between perceived psychological stress and disease activity, whereas noncarriers exhibited a significant positive correlation.

The authors conclude that psychological stress reactivates inflammatory memory in arthritic joints via a novel brown adipose tissue-IL-6-fibroblast axis independent of lymphocyte-mediated pathways. Pharmacological targeting of beta3-adrenergic receptors or downstream signaling components offers a promising complementary therapeutic strategy to prevent stress-induced arthritis flares without requiring broad systemic immunosuppression.

Link to the article: https://www.science.org/doi/10.1126/sciadv.aec9257?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

Tamura, J., Tanaka, S., Etori, K., Hashiba, D., Kameda, S., Tomikawa, A., Kikuchi, R., Takahashi, T., Saku, A., Kawashima, H., Nakamura, J., Ohtori, S., Kagami, S.-I., Hirose, K., & Nakajima, H. (2026). Fibroblast-like synoviocytes exacerbate autoimmune arthritis upon psychological stress in an IL-6–dependent manner. Science Advances, 12(42), eaec9257. https://doi.org/10.1126/sciadv.aec9257