Splenic erythrophagocytosis is regulated by ALX/FPR2 signaling.

Abstract

Maintaining a healthy pool of circulating red blood cells (RBCs) is essential for adequate perfusion, as even minor changes in the population can impair oxygen delivery, resulting in serious health complications including tissue ischemia and organ dysfunction. This responsibility largely falls to specialized macrophages in the spleen, known as red pulp macrophages, which efficiently take up and recycle damaged RBCs. However, questions remain regarding how these macrophages are acutely activated to accommodate increased demand. Proresolving lipid mediators stimulate macrophage phagocytosis and efferocytosis but their role in erythrophagocytosis has only recently been described. To investigate the role of lipid mediators on red pulp macrophage function, we targeted the ALX/FPR2 signaling pathway, as this receptor binds multiple lipid mediator ligands eliciting potent macrophage responses. We found that mice with Fpr2 deletion exhibited disrupted erythrocyte homeostasis resulting in an aged RBC pool, decreased markers of splenic RBC turnover, and altered splenic macrophage phenotype characterized by changes in heme metabolism. Upon activation of ondemand erythrophagocytosis, production of the ALX/FPR2 ligand, lipoxin A4 (LXA4), was induced in the spleen while receptor-deficient animals were unable to efficiently clear damaged RBCs, a defect that was conserved in mice with myeloid-specific FPR2 deletion. Similarly, mice lacking the LXA4 biosynthetic enzyme displayed defective erythrophagocytosis that was rescued with LXA4 administration. These results indicate that the ALX/FPR2 signaling axis is necessary for maintenance of RBC homeostasis and LXA4 activation is a critical aspect of the red pulp macrophage response to acute erythroid stress.