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Peritoneal dialysis (PD) is one of the effective replacement therapies for end-stage renal disease (ESRD). After long-term peritoneal dialysis (LPD) treatment, about 50% of patients will develop peritoneal fibrosis and ultrafiltration failure. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that express an evolutionarily conserved semi-invariant T cell antigen receptor (TCR) repertoire and a pathogenic role in inflammatory diseases has also recently emerged, with consistent data reporting altered MAIT cell-functions during acute and chronic inflammatory injury.
We performed FACS and scRNA-seq analysis on peritoneal lavage fluid (PLF) from health donors and patients with ESRD, as well as PD effluent from patients undergoing short-term and long-term PD. We conduct PD-model on MAIT-deficient Mr1-/- mouse to illustrated the fibrogenetic function of MAIT in vivo and also using the inhibitor of MAIT activation (Ac-6-FP) for further treatment. Combining the results of immunofluorescence, cell-communication analysis of scRNA-seq data, we revealed the target cell type of MAIT in peritoneum. And we used bulk RNA-seq analysis of Mr1-/- PD model mice, flow cytometry and seahorse assay of peritoneal mesothelial cells after co-culture experiments to illustrated downstream pathways of TCRVα7.2-MR1 mediated MAIT-mesothelial cells crosstalk.
We discovered that peritoneal MAIT cells displayed an inflammatory phenotype (MAIT17) and correlate with decline in peritoneal function after Long-term PD treatment. We also found that MAIT cells mainly target mesothelial cells in peritoneum through TCRVα7.2-MR1 crosstalk to mediated PD-related fibrosis. Contact and transwell co-culture of MAIT and mesothelial cells revealed that MAIT promotes MMT of mesothelial cells through physical contact rather than cytokines, which could be ameliorated by MR1 antibody. Combining results of Immunofluorescence, bulk RNA-seq analysis of Mr1-/- PD model mice, flow cytometry and seahorse assay of mesothelial cells after co-culture experiments, we further discovered that active MAIT could promote the glycolysis in mesothelial cells by activating the mTORC1 signaling pathway. In addition, our study also proved that inhibitor of MAIT activation (Ac-6-FP) could significantly alleviated PD-related fibrosis in mice via inhibiting MAIT activation.
Long-term peritoneal dialysis can give rise to MAIT17 activation and increase their infiltration in peritoneum. MAIT binds to MR1 receptor in the peritoneal mesothelial cells to activate the mTORC1 signaling pathway, induce the hyper-glycolysis via mTORC1 pathway, while the inhibiting MAIT activation may serve as a potential treatment method for peritoneal fibrosis.