Stress-induced heme metabolic disorder in peripheral B cells contributes to depressive-like behaviors in male mice

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.