Ozone-primed neutrophils promote early steps of tumour cell metastasis to lungs by enhancing their NET production.

Abstract

Air pollution, including particulates and gazes such as ozone (O₃), is detrimental for patient's health and has repeatedly been correlated to increased morbidity and mortality in industrialised countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O₃ exposure and metastatic dissemination to lungs. To outline the mechanisms through which pulmonary O₃ exposure modulates metastasis kinetics in an experimental mouse model of O₃ exposure. Metastatic responses to pulmonary O₃ exposure were assessed using a reliable experimental mouse model of concomitant pulmonary O₃ exposure and tumour cell injection. Roles of neutrophils in O₃-induced lung metastasis were highlighted using blocking anti-Ly6G antibodies; moreover, the implication of neutrophil extracellular traps (NETs) in metastatic processes was evaluated using <i>MRP8cre-Pad4lox/lox</i> mice or by treating mice with DNase I. Pulmonary O₃ exposure strongly facilitates the establishment of lung metastasis by (1) Inducing a pulmonary injury and neutrophilic inflammation, (2) Influencing very early steps of metastasis, (3) Priming neutrophils' phenotype to release NETs that favour tumour cell colonisation in lungs. The ability of O₃-primed neutrophils to enhance lung colonisation by tumour cells was proven after their adoptive transfer in Balb/c mice unexposed to O₃. Pulmonary neutrophils induced by O₃ promote metastatic dissemination to lungs by producing NETs. These findings open new perspectives to improve treatment and prevention strategies in patients affected by metastatic diseases.