Rictor Ameliorates Acute Antibody-Mediated Rejection Following Kidney Transplantation by Suppressing Macrophage M1 Polarization Through p65-NLRP3 Axis.

Antibody-mediated rejection (ABMR) represents the leading cause of kidney allograft failure over a long term after transplantation. Early infiltration of macrophages predicts the adverse outcome of grafts, yet the underlying mechanisms remain to be elucidated. Significant infiltration of M1 macrophages and upregulation of Rictor in macrophages are observed in ABMR allografts. Deficiency of Rictor in macrophages exacerbates histological injury and shortens the survival of ABMR allografts by promoting macrophage M1 polarization. Additionally, loss of Rictor in primary bone marrow-derived macrophages facilitates NLRP3 inflammasome activation through activating NF-κB. Mechanistically, Rictor upregulates E3 ubiquitin ligase SOCS1 to enhance K48-linked ubiquitination of p65, thereby suppressing macrophage M1 polarization. Taken together, Rictor ameliorates acute ABMR following kidney transplantation by suppressing macrophage M1 polarization through the p65-NLRP3 axis and may serve as a therapeutic target for ABMR.