GABA signaling enforces intestinal germinal center B cell differentiation
Yuexia Liao, Lijuan Fan, Peng Bin, Congrui Zhu, Qingyi Chen, Yepeng Cai, Jielin Duan, Qian Cai, Wei Han, Shizhen Ding, Xiangyu Hu, Yiran Zhang, Yulong Yin, Wenkai Ren
Abstract
B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.