Yin Yuye, Li Bin, Du Longfei, Wu Shusheng
College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, China.
Institute of Comparative Medicine, College of Veterinary Medicine, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, China.
Prog Neurobiol. 2025 Aug;251:102800. doi: 10.1016/j.pneurobio.2025.102800. Epub 2025 Jun 21.
Major depressive disorder (MDD) is a common and burdensome psychiatric illness with high rates of recurrence. Most of the current therapeutic drugs for depression mainly achieve their antidepressant effect by tuning the landscape of neurotransmitters in the central nervous system (CNS). However, almost half of patients with MDD cannot fully benefit from these available treatments. Consequently, it is urgent to find novel therapeutic targets for the treatment of MDD. Peripheral B lymphocytes have been reported as a major contributor to the occurrence of stress-induced depression. However, the pathological role and underlying regulatory mechanism of peripheral B cells in MDD have not been well established. Here, we show that peripheral B cells are significantly infiltrated into the CNS of male mice after exposure to chronic unpredictable mild stress (CUMS). Adoptive transfer of B cells from CUMS mice into B-cell-deficient male mice could significantly induce higher severity depressive symptoms than adoptive transfer of B cells from control mice. The lack of B cells protects male mice from CUMS-induced neuroinflammation and depressive-like behaviors. Interestingly, the pathological B cells in CUMS mice are characterized by increased heme biosynthesis, whereas its inhibition can ameliorate depressive-like behaviors in B-cell-deficient mice that received pathological B cells from CUMS mice. Our findings suggest a critical role of the heme biosynthesis in B cells for contributing to the pathogenesis of depression and indicate that these pathological B cells featuring high heme may be a promising immune target for the development of precision medicine approaches in MDD.
重度抑郁症（MDD）是一种常见且负担沉重的精神疾病，复发率很高。目前大多数治疗抑郁症的药物主要通过调节中枢神经系统（CNS）中神经递质的格局来实现其抗抑郁作用。然而，几乎一半的MDD患者无法从这些现有治疗中充分获益。因此，迫切需要找到治疗MDD的新治疗靶点。外周B淋巴细胞已被报道是应激诱导抑郁症发生的主要因素。然而，外周B细胞在MDD中的病理作用和潜在调节机制尚未完全明确。在此，我们表明，暴露于慢性不可预测轻度应激（CUMS）后，外周B细胞会显著浸润到雄性小鼠的中枢神经系统中。将CUMS小鼠的B细胞过继转移到B细胞缺陷的雄性小鼠中，比将对照小鼠的B细胞过继转移能显著诱导更严重的抑郁症状。缺乏B细胞可保护雄性小鼠免受CUMS诱导的神经炎症和抑郁样行为的影响。有趣的是，CUMS小鼠中的病理性B细胞的特征是血红素生物合成增加，而抑制血红素生物合成可改善接受来自CUMS小鼠的病理性B细胞的B细胞缺陷小鼠的抑郁样行为。我们的研究结果表明，B细胞中的血红素生物合成在抑郁症发病机制中起关键作用，并表明这些具有高血红素的病理性B细胞可能是MDD精准医学方法开发中一个有前景的免疫靶点。
