Exosomal miR‐181d‐5p Derived from Rapamycin‐Conditioned MDSC Alleviated Allograft Rejection by Targeting KLF6

Abstract

Immune rejection and side effects of long‐term administration of immunosuppressants are the two major obstacles to allograft acceptance and tolerance. The immunosuppressive extracellular vesicles (EVs)‐based approach has been proven to be effective in treating autoimmune/inflammatory disorders. Herein, the anti‐rejection advantage of exosomes (Rapa‐Exo) from rapamycin‐conditioned myeloid‐derived suppressor cells (MDSCs) over exosomes (Exo‐Nor) from the untreated MDSCs is shown. The exosomal small RNA sequencing and loss‐of‐function assays reveal that the anti‐rejection effect of Rapa‐Exo functionally relies on miR‐181d‐5p. Through target prediction and double‐luciferase reporter assay, Kruppel‐like factor (KLF) 6 is identified as a direct target of miR‐181d‐5p. Finally, KLF6 knockdown markedly resolves inflammation and prolongs the survival of corneal allografts. Taken together, these findings support that Rapa‐Exo executes an anti‐rejection effect, highlighting the immunosuppressive EVs‐based treatment as a promising approach in organ transplantation.