MAIT Cell-Mediated Immune Mechanisms of Dialysis-Induced Peritoneal Fibrosis and Therapeutic Targeting.

Abstract

BACKGROUND Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis (PD) and abdominal surgeries, yet effective treatments remain elusive. Given the known roles of mucosal-associated invariant T (MAIT) cells in immune responses and fibrotic diseases, we investigated their involvement in PD-induced peritoneal fibrosis to identify potential therapeutic targets. METHODS We employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to characterize the activation and function of peritoneal MAIT cells in patients undergoing long-term PD. Our investigation focused on the molecular pathways activated by these cells, particularly the MHC class I-related protein 1 (MR1)-mediated interaction with mesothelial cells and subsequent activation of the mTORC1 signaling pathway. We further assessed the impact of inhibiting MAIT cells on fibrogenesis using both in vitro models and Mr1 knockout mice. RESULTS Our study revealed that long-term PD significantly enhanced the activation of MAIT cells, particularly the pro-inflammatory MAIT17 subtype. These activated cells contributed to peritoneal fibrogenesis by binding to the MR1 receptor on mesothelial cells, which triggered hyperglycolysis through the mTORC1 pathway, ultimately leading to fibrogenesis. Notably, we demonstrated that blocking the MR1-MAIT interaction, either through genetic knockout or pharmacological inhibition with acetyl-6-formylpterin (Ac-6-FP), effectively mitigated fibrosis. CONCLUSIONS This study identified MAIT cells as crucial drivers of PD-induced peritoneal fibrosis.