Differential contribution of bone marrow derived-monocytes to the lung tissue resident alveolar macrophages and persistent lung inflammation with chronic air pollution exposure

Chronic exposure to ambient particulate matter <2.5µ (PM2.5) has been linked to cardiopulmonary disease. Tissue-resident (TR) alveolar macrophages (AF) are long lived, self-renew and critical to the health impact of inhalational insults. There is inadequate understanding of the impact of PM2.5 exposure on nature/time course of transcriptional responses and the proliferation/maintenance of AF including the contribution from bone marrow (BM) over chronic time periods. We investigated the effects of exposure to real-world concentrated PM2.5 or filtered air (FA) in chimeric (CD45.2/CD45.1) mice. Here, we show that PM2.5 exposure induces an influx of BM-derived monocytes to lungs at 4-weeks, with no contribution to TR-AF population. Chronic (32-weeks) PM2.5 exposure resulted in enhanced apoptosis (Annexin V+) and decreased proliferation (BrdU+) of TR-AF and presence of BM-AF in inflamed lungs. RNA-seq analysis of flow sorted TR-AF and BM-AF from 4 and 32-weeks exposed mice, revealed a unique time dependent pattern of differentially expressed genes, with PM2.5 exposure with a pro-inflammatory bias. PM2.5 exposure resulted in pulmonary fibrosis and reduced alveolar fraction which corresponded to protracted lung inflammation. Our findings suggest a time dependent PM2.5 entrainment of a BM-derived monocytes infiltration into PM2.5 exposed lungs with an inflammatory phenotype, that together with enhanced apoptosis of TR-AF and pro-inflammatory polarization may contribute to perpetuation of chronic inflammation and lung fibrosis. Overall design: RNA sequencing of alveolar macrophages and monocytes of CD45.1 and CD45.2 origin from PM2.5 or FA exposed mice for 4 and 32 weeks.