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

Abstract

Chronic exposure to particulate matter < 2.5µ (PM 2.5) has been linked to cardiopulmonary disease. Tissue-resident (TR) alveolar macrophages (AΦ) are long-lived, self-renew and critical to the health impact of inhalational insults. There is an inadequate understanding of the impact of PM 2.5 exposure on the nature/time course of transcriptional responses, self-renewal of AΦ, and the contribution from bone marrow (BM) to this population. Accordingly, we exposed chimeric (CD45.2/CD45.1) mice to concentrated PM 2.5 or filtered air (FA) to evaluate the impact on these end-points. PM 2.5 exposure for 4-weeks induced an influx of BM-derived monocytes into the lungs with no contribution to the overall TR-AΦ pool. Chronic (32-weeks) PM 2.5 exposure on the other hand while associated with increased recruitment of BM-derived monocytes and their incorporation into the AΦ population, resulted in enhanced apoptosis and decreased proliferation of TR-AΦ. RNA-seq analysis of isolated TR-AΦ and BM-AΦ from 4-and 32-weeks exposed mice revealed a unique time-dependent pattern of differentially expressed genes. PM 2.5 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 AΦ population of PM 2.5 exposed mice, that together with enhanced apoptosis of TR-AΦ and reorganization of transcriptional responses, could collectively contribute to the perpetuation of chronic inflammation. Exposure to ambient air pollution, specifically particulate matter < 2.5 µm in diameter (PM 2.5) is the world's leading environmental risk factor for non-communicable diseases, including respiratory disorders. Inhalational exposure to PM 2.5 has been implicated in adverse health outcomes across the lifespan, including impaired lung development, acceleration of age-related decline in lung function, pulmonary and cardiovascular disorders 1. The alveolar macrophage (AΦ) population in the lung are the first line of defense, responsible for the phagocytosis of inhaled particles and maintenance of immune homeostasis in the lung.

LincRNA-Cox2 functions to regulate inflammation in alveolar macrophages during acute lung injury

“…We found that transplanting WT BM into our lincRNA-Cox2 mutant mice completely rescued the neutrophil and cytokine/chemokine phenotype in the BAL (Figure 7B-K). While we aimed to determine if lincRNA-Cox2 functions either through resident (SiglecF+) or recruited (Siglec F-) alveolar macrophages, we found that both populations were composed of >70% donor BM (SFigure 8I-J) indicating that radiation obliterated resident SiglecF+ alveolar cells which become repopulated with donor cells from the bone marrow (Guilliams et al , 2013; Hashimoto et al , 2013; Misharin et al , 2017; Collins et al , 2020; Gangwar et al , 2020). These experiments enable us to conclude that lincRNA-Cox2 expression originating from the bone marrow can function to control immune responses in the lung, since BM derived immune cells transplanted into lincRNA-Cox2 mutant mice are able to rescue the phenotype driven by loss of lincRNA-Cox2 in the lung.…”

Dipeptidyl Peptidase 4/Midline‐1 Axis Promotes T Lymphocyte Motility in Atherosclerosis

“…For RNA sequencing, total RNA was sent to Novogene for sequencing on an Illumina NovaSeq platform and analyzed as described earlier. [27] Hyperinsulinemic-Euglycemic Clamp: The hyperinsulinemiceuglycemic clamp experiment was performed as previously described. [28] Briefly, jugular vein-cannulated mice were acclimated to restrainers (3 h per day for 3 days) before the clamp experiment.…”

Modulation of pulmonary immune function by inhaled cannabis products and consequences for lung disease

“…The lung has two macrophage populations: alveolar macrophages and interstitial macrophages (IMs), which differ based on origin and function. Alveolar macrophages are long-lived, embryonically-derived cells that self-renew to maintain their population [ 136 ]. In response to injury, bone marrow monocytes also migrate to the lungs and differentiate into macrophages to restore the alveolar macrophage pool.…”