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

IF 13.9 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2026-10-16 DOI:10.1126/sciadv.aec9257

Jun Tamura, Shigeru Tanaka, Keishi Etori, Daisuke Hashiba, Shuhei Kameda, Atsuko Tomikawa, Ryo Kikuchi, Tatsuro Takahashi, Aiko Saku, Hirotoshi Kawashima, Junichi Nakamura, Seiji Ohtori, Shin-Ichiro Kagami, Koichi Hirose, Hiroshi Nakajima

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Abstract

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.

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成纤维细胞样滑膜细胞以il -6依赖的方式在心理应激下加剧自身免疫性关节炎

心理压力影响免疫系统并加剧自身免疫性疾病，如类风湿关节炎（RA），但缓解期组织炎症的机制尚不清楚。在这里，我们表明在缓解期间，管约束应力加剧了小鼠关节炎模型的关节炎症。这种恶化需要交感神经激活后棕色脂肪组织（BAT）产生的白细胞介素-6 （IL-6）。表达IL-6受体亚基gp130的成纤维细胞样滑膜细胞是关键的介质，因为IL-6刺激这些细胞产生中性粒细胞趋化剂CXCL1。β3-肾上腺素能受体的药物阻断可显著减轻应激性关节炎的发作。在RA患者中，ADRB3功能低下的Trp64Arg变体携带者显示心理压力与疾病活动之间没有正相关，而非携带者则有。这些发现确定了在关节炎中重新激活炎症记忆的bat - il -6成纤维细胞轴，并表明靶向应激反应途径可能为当前RA治疗提供补充治疗策略，而不会广泛抑制全身免疫。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.