Fig. 1: The effects of EPO on macrophages.

EPO regulates the polarization of macrophages via shifting them to M2 phenotype and exerts anti-inflammatory effects. Activation of TLR on macrophages leads to upregulation of inflammatory mediators and polarization to M1 phenotype, which aggravates tissue injury. EPO shifts macrophages to M2 phenotype via EPOR/Jak2/STAT3/STAT6 signaling pathway in the presence of IL-4. Meanwhile, EPO inhibits NF-κB p65 activation via EPOR/Jak2/PI3K pathway. EPO also plays a vital role in clearing apoptotic cells and cell debris. S1P released from apoptotic cells and hypoxia upregulate EPO and EPOR expression via HIF complex. EPO signaling increases the levels of phagocytic receptors through PPARγ pathway and facilitates phagocytosis of apoptotic cells. EPO erythropoietin, TPR tissue-protective receptor, S1P sphingosine 1-phosphate, HIF hypoxia-inducible factor.