Targeting soluble PD-1 alleviates peritoneal fibrosis by modulating PD-L1 recycling and mesothelial-mesenchymal transition

BACKGROUND: Peritoneal fibrosis (PF) is a major cause of technique failure in long-term peritoneal dialysis (PD) patients, driven by a chronic microinflammatory state. While T-cell activation is implicated, the role of soluble programmed death-1 (sPD-1), primarily derived from activated T cells, in PF pathogenesis remains elusive. METHODS: We initially analyzed serum sPD-1 levels in PD patients and employed a mice PF model induced by high-glucose dialysate and lipopolysaccharide (LPS). The functional impact of sPD-1 on the progression of PF was assessed through the administration of a PD-L1 fusion protein, or engineered exosomes designed to adsorb sPD-1. RESULTS: Serum sPD-1 levels were significantly elevated in long-term PD patients and were positively correlated with dialysis duration and markers of fibrosis, but inversely correlating with peritoneal function. In mice, exogenous sPD-1 exacerbated PF, whereas blockade with a PD-L1 fusion protein or sPD-1-adsorbing engineered exosomes markedly attenuated fibrosis, reduced T-cell infiltration, and preserved peritoneal function. Mechanistically, sPD-1 bound to PD-L1 on PMCs, triggering clathrin-mediated endocytosis. This interaction diverted PD-L1 from the lysosomal degradation pathway towards the Rab11-positive recycling endosome pathway, resulting in sustained upregulation of surface PD-L1 expression. This aberrant PD-L1 recycling activated pro-fibrotic signaling, culminating in mesothelial-to-mesenchymal transition (MMT). CONCLUSION: sPD-1 is a pivotal mediator linking peritoneal microinflammation to fibrosis by modulating the endocytic fate of PD-L1 in mesothelial cells. Targeting sPD-1, particularly using engineered exosomes or a PD-L1 fusion protein, represents a promising therapeutic strategy for preventing and treating peritoneal fibrosis.