Abstract Rationale Since the 1950s, micro- and nanoplastics (MNPs) have become omnipresent, representing a novel environmental hazard which continually deposits in our airways. Concurrently, there has been a rapid increase in lung cancer in never-smokers which cannot be attributed to genetic alterations. Although MNPs have been identified in the lung, if and how they promote lung disease and/or cancer remains unknown. Methods Mice were administered intranasal MNPs and lung function and pathology determined. Pulmonary macrophages (pMacs) were isolated for RNA-sequencing. Additional cohorts were inoculated with Lewis lung carcinoma (LLC) cells post-MNPs and tumor burden measured. Human monocyte-derived macrophages and macrophage cell lines were co-cultured in vitro with 0.02-10μm polystyrene, polyamine, and polyethylene MNPs and assessed for antigen processing, T cell stimulation, tumor phagocytosis, and bioenergetics. MNP-treated human precision-cut lung slices (PCLS) were assessed for markers of EMT and fibrosis. Results After 7-days, murine pMacs retained MNPs and upregulated pro-inflammatory IRF8/JUN/NF-kb with loss of muscarinic acetylcholine signaling, indicative of unchecked inflammation associated with fibrosis and EMT. When co-cultured in vitro, MNPs induced FOXM1 and IL-13/STAT6/ZEB1 signaling programs in macrophages associated with tissue repair and cancer metastasis. By contrast, diesel exhaust particulate (DEP) induced AHR signaling due to oxidative stress. Mechanistically, intracellular MNPs displace mitochondrial in macrophages, reducing mitochondrial mass, polarization, and oxidative phosphorylation which may be partially restored with the AMPK agonist AICAR. Interestingly, compared to DEP, MNP-treated macrophages increase expression of the mitochondrial genes ND6 and ATP8, subunits of the electron transport chain, potentially compensating for bioenergetic disruption. Pretreatment with MNPs reduced the ability of macrophages to phagocytose tumor cells in a dose and size dependent manner. MNPs impaired protein antigen processing in macrophages and T cell stimulation due to reduced antigen uptake into MNP loaded phagolysosomes. Additionally, MNPs induced expression of PD-1/PD-L1 on macrophages, which inhibited T cell stimulation and could be restored by antibodies blocking PD-1/PD/L1. MNPs embed within PCLS resulting in the loss of E-cadherin and gain of N-cadherin/α-SMA after 7-days. Finally, preliminary findings suggest that MNPs induce restrictive changes in the lung with decreased FEV0.05, and FEV0.1/FVC, and increase tumor burden in mice following LLC challenge. Conclusions These findings indicate that MNPs impair macrophages via unique mechanisms which include bioenergetic dysfunction. Loss of anti-tumor capabilities in MNP-laden macrophages may compromise cancer surveillance and elimination. As such, MNPs may have the potential to increase susceptibility to lung disease independent of the conventional mechanisms of inflammation and oxidative stress. This abstract is funded by: Department of Defense, Department of Cardiothoracic Surgery University of Pittsburgh School of Medicine
Soloff et al. (Fri,) studied this question.