CD83 mediates the inhibitory effect of the S1PR1 agonist CYM5442 on LPS-induced M1 polarization of macrophages through the ERK-STAT-1 signaling pathway.

Macrophages possess M1/M2 polarization, which perform an essential role in immunology and inflammation studies. However, few studies have investigated the specific molecules involved in the polarization process beyond its induction and characterization. Here, we determined that the molecule S1PR1 regulates M1 polarization in macrophages and that the surface marker CD83 is involved in this process. The S1PR1 agonist CYM5442 specifically increases CD83 expression in macrophages. Although the agonist CYM5442 and LPS regulate CD83 differently in macrophages, they have a synergistic effect that enhances CD83 expression. Notably, CYM5442 does not act synergistically with IL-4 regarding CD83 expression and does not affect IL-4-induced macrophage M2 polarization. Furthermore, CYM5442 inhibits the expression of LPS-induced inflammatory cytokines and the phosphorylation of ERK1/2 and STAT-1 in macrophages. However, this inhibition was significantly diminished or absent when CD83 is deficient, highlighting the importance of CD83 in mediating S1PR1 signaling in LPS-induced M1 polarization of macrophages. Overall, our findings provide valuable insights into the molecular mechanisms underlying macrophage polarization, particularly the roles of S1PR1 and CD83 in modulating inflammatory responses.