INSL3 promotes macrophage polarization to an immunosuppressive phenotype via the cAMP downstream signaling pathway and Akt/ mTOR pathway

Insulin-like peptide 3 (INSL3) is a small peptide hormone produced almost exclusively by testicular Leydig cells in males and thus serves as an essential biomarker of the maturation and functionality of these cells. Accumulated evidence suggests that INSL3 is a crucial factor affecting testicular descent during fetal development by regulating the growth of the gubernaculum. However, the physiological roles of INSL3 in adults remain unclear. Here, we reported that relaxin family peptide 2 (RXFP2), the receptor of INSL3, is expressed on macrophages, and treatment with INSL3 can promote M2 macrophage polarization via the Akt/mTOR/S6K and PKA/CREB pathways. In addition, INSL3 can inhibit macrophage phagocytosis and promote their migration via the Epac and PKA signaling pathways, respectively. These findings reveal a new role for INSL3 in regulating macrophage function and shed new light on our understanding of the role of INSL3 in adulthood.