The Kidney-immune Axis: How Erythropoietin Regulates Tolerance and Rejection

Area of Science:

• Immunology
• Nephrology
• Endocrinology

Background:

• Erythropoietin (EPO) is primarily known as a kidney-derived hormone regulating red blood cell production.
• The kidney plays a crucial role in immune tolerance and is susceptible to immune-mediated injury.
• Emerging evidence highlights EPO's involvement in complex kidney-immune system interactions.

Purpose of the Study:

• To review experimental and clinical data on EPO's role in adaptive and innate immunity.
• To explore EPO's influence on immune tolerance and rejection processes.
• To discuss the therapeutic potential of the EPO-EPOR axis in transplantation and oncology.

Main Methods:

• Review of experimental and clinical studies on EPO and its receptor (EPOR).
• Analysis of EPO's effects on T cell subsets (effector T cells, regulatory T cells, TH17, TFH/TFR).
• Examination of EPO's impact on macrophage function and trained immunity.
• Evaluation of EPO's role in lupus and posttransplant erythrocytosis models.

Main Results:

• EPO restrains effector T cells and promotes regulatory T cells via TGF-β, inhibiting TH17 differentiation and skewing TFH/TFR balance towards regulation.
• EPO signaling in macrophages limits inflammation, promotes M2-like phenotypes, enhances apoptotic cell clearance, and counteracts trained immunity.
• Endogenous EPO acts as a physiological mechanism for peripheral immune tolerance in lupus and posttransplant models.
• EPO-EPOR axis activation in tumor-associated macrophages contributes to immune suppression and resistance to immune checkpoint inhibitors.

Conclusions:

• EPO acts as a critical regulator of renal and systemic immunity, influencing both tolerance and rejection.
• Harnessing the EPO-EPOR pathway offers potential strategies for promoting transplant tolerance.
• Modulating EPO signaling may help overcome immune suppression in tumors and improve immunotherapy efficacy.