Department of Sports Medicine, the First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China.
Department of Rehabilitation Medicine, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Physical Education, Huanghuai University, Zhumadian, China.
Brain Behav Immun. 2024 Mar;117:412-427. doi: 10.1016/j.bbi.2024.02.006. Epub 2024 Feb 4.
Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.
类风湿关节炎（RA）患者普遍存在抑郁症状。另一方面，与抑郁共病与 RA 的预后更差相关。然而，RA 和抑郁共病的潜在机制知之甚少。仍需要阐明哪个脑区在 RA 患者的抑郁发展中起着关键作用，以及大脑的变化是否会影响 RA 症状的病理发展。在这里，我们通过结合临床和动物模型研究，表明在 RA 患者中，抑郁程度与 RA 疾病活动的严重程度显著相关，并影响患者的生活质量。胶原抗体诱导的关节炎（CAIA）RA 小鼠模型也会出现类似抑郁的行为，同时伴随着外侧缰核（LHb）中血管破坏的基因表达改变，而 LHb 是一个对处理负面情绪至关重要的脑区。重要的是，抑制 LHb 不仅可以缓解类似抑郁的行为，还可以迅速缓解 RA 症状并改善与 RA 相关的病理变化。总之，我们的研究强调了 LHb 过度活跃对 RA 和抑郁共病的关键但以前被忽视的贡献，表明联合 RA 治疗靶向 LHb 可能是治疗伴有抑郁的 RA 患者的一种有前途的策略。
