Real-ambient PM2.5 exposure disrupts hematopoietic homeostasis via HIF-1α-driven myeloid skewing and promotes organ inflammation

Abstract Environmental pollutants like PM2.5 threaten hematopoietic homeostasis, yet how real-world exposure disrupts blood cell production, especially locally in the lung and systemically in the bone marrow (BM), remains poorly understood. Previous studies often used artificial particles or lacked mechanistic insights into systemic effects. Hypoxia-inducible factor-1alpha (HIF-1α) is essential for hematopoietic stem cell (HSC) maintenance. Herein, we utilized a real-ambient PM2.5 exposure system and conducted a detailed characterization of hematopoietic and downstream immune cell populations in mice with myeloid lineage-specific knockout of HIF-1α (mHIF-1α −/−) and their wild-type littermate controls. Our findings demonstrate that real-ambient PM2.5 exposure induces a HIF-1α-dependent myeloid-biased hematopoiesis within both the lung and BM. This bias results in an accumulation of mature myeloid cells, particularly neutrophils and macrophages, in peripheral organs such as the liver and spleen. Critically, this cellular redistribution precipitates inflammatory injury in a HIF-1α-dependent manner. These results provide novel insights into how environmental contaminants, exemplified by PM2.5, perturb hematopoiesis, highlighting the critical role of HIF-1α in mediating lineage-specific hematopoietic responses and subsequent inflammatory sequelae.