Differential contribution of bone marrow-derived infiltrating monocytes and resident macrophages to persistent lung inflammation in chronic air pollution exposure

Chronic exposure to particulate matter <2.5 mu (PM2.5) has been linked to cardiopulmonary disease. Tissue-resident (TR) alveolar macrophages (A Phi) are long-lived, self-renew and critical to the health impact of inhalational insults. There is an inadequate understanding of the impact of PM2.5 exposure on the nature/time course of transcriptional responses, self-renewal of A Phi, and the contribution from bone marrow (BM) to this population. Accordingly, we exposed chimeric (CD45.2/CD45.1) mice to concentrated PM2.5 or filtered air (FA) to evaluate the impact on these end-points. PM2.5 exposure for 4-weeks induced an influx of BM-derived monocytes into the lungs with no contribution to the overall TR-A Phi pool. Chronic (32-weeks) PM2.5 exposure on the other hand while associated with increased recruitment of BM-derived monocytes and their incorporation into the A Phi population, resulted in enhanced apoptosis and decreased proliferation of TR-A Phi. RNA-seq analysis of isolated TR-A Phi and BM-A Phi from 4- and 32-weeks exposed mice revealed a unique time-dependent pattern of differentially expressed genes. PM2.5 exposure resulted in altered histological changes in the lungs, a reduced alveolar fraction which corresponded to protracted lung inflammation. Our findings suggest a time-dependent entrainment of BM-derived monocytes into the A Phi population of PM2.5 exposed mice, that together with enhanced apoptosis of TR-A Phi and reorganization of transcriptional responses, could collectively contribute to the perpetuation of chronic inflammation.