Reversible disruption of proresolving lipid mediator pathways and erythroid homeostasis by PM2.5

Abstract

Ambient particulate matter (PM2.5) exposure is a major environmental risk factor for cardiopulmonary disease, but its effects on erythroid homeostasis remain incompletely understood. Although prior in vitro work indicates that PM2.5 can damage circulating red blood cells (RBCs), whether exposure alters erythropoiesis and the coordinated clearance of senescent RBCs has not been fully explored. Using a mouse model of whole-body exposure to concentrated ambient PM2.5 (CAP), we investigated associations between inhaled PM on erythroid output, splenic macrophage function, and lipid mediator signaling. CAP exposure was associated with suppressed erythropoietin levels, reduced circulating reticulocytes, and decreased erythroid precursor populations in the bone marrow, consistent with impaired erythropoiesis. Despite preserved splenic architecture, CAP-exposed mice exhibited reduced splenic iron and heme content, consistent with diminished erythrocyte turnover and processing. Targeted lipidomic profiling revealed broad suppression of proresolving lipid mediators in the spleen, with lipoxin A4 (LXA4) among the most consistently reduced species. Expression of the LXA4 receptor, ALX/FPR2, was also downregulated with prolonged exposure. Importantly, removal of CAP and return to filtered air resulted in normalization of splenic lipid mediator profiles, restoration of LXA4 levels, and recovery of erythroid parameters, including reticulocyte abundance and RBC stress markers. Together, these findings suggest that altered resolution signaling contributes to PM2.5-induced disruption of erythroid homeostasis and implicate macrophage–lipid mediator pathways in the hematologic response to environmental stress.