Abstract：
Signal-regulatory protein alpha (SIRPα) has recently been found to be highly expressed in podocytes and is essential for maintaining podocyte function. However, its immunoregulatory function in podocytes remains elusive. Here, we report that SIRPα controls podocyte antigen presentation in specific T cell activation via inhibiting spleen tyrosine kinase (Syk) phosphorylation. First, podocyte SIRPα under lupus nephritis (LN) conditions is strongly downregulated. Second, podocyte-specific deletion of SIRPα exacerbates renal disease progression in lupus-prone mice, as evidenced by an increase in T cell infiltration. Third, SIRPα deletion or knockdown enhances podocyte antigen presentation, which activates specific T cells, via enhancing Syk phosphorylation. Supporting this, Syk inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN.
摘要：
最近发现信号调节蛋白α（SIRPα）在足细胞中高度表达，对于维持足细胞功能至关重要。然而,其在足细胞中的免疫调节功能仍然难以捉摸。这里,我们报道SIRPα通过抑制脾酪氨酸激酶(Syk)磷酸化来控制特异性T细胞活化中的足细胞抗原呈递。首先,在狼疮性肾炎（LN）条件下足细胞SIRPα强烈下调。第二,SIRPα的足细胞特异性缺失加剧了狼疮易感小鼠的肾脏疾病进展，如T细胞浸润增加所证明的。第三，SIRPα缺失或敲低增强足细胞抗原呈递，激活特定的T细胞，通过增强Syk磷酸化。支持这一点,Syk抑制剂GS-9973可防止足细胞抗原呈递，导致T细胞活化减少和减轻由SIRPα敲低或缺失引起的肾脏疾病。我们的发现揭示了SIRPα缺失在促进足细胞抗原呈递以激活LN中的特异性T细胞免疫应答中的免疫调节作用。
