Macrophage-epithelial cells crosstalk and the role of CCL2-CCR2 axis in single-walled carbon nanotubes-induced lung inflammation and fibrosis

Environmental and occupational exposure to carbon nanotube (CNT) raises concerns over their safety and adverse health impacts, especially lung inflammation and fibrosis. Immune cells and epithelial cells within alveoli interact with each other to maintain lung homeostasis. To date, the contribution of lung macrophage-epithelial cells crosstalk to single-walled CNT (SWCNT)-caused lung injury and underlying mechanisms have not been systematically investigated. Here, we established a mice model of lung exposure to SWCNT and found that SWCNT induced M1-typed lung macrophages polarization during inflammation stage and abnormal epithelium regeneration during fibrosis stage, characterized by impaired alveolar epithelial type Ⅱ (AT2) cells to alveolar epithelial type Ⅰ (AT1) cells transition. Mechanistically, conditioned medium experiments combined with chemokines CCL2 siRNA intervene revealed that damaged lung epithelial cells-derived CCL2 by SWCNT activated CCR2 in macrophages, subsequently polarizing to M1 state. In vivo experiments further demonstrated CCL2-CCR2 axis regulated SWCNT-polarized M1 lung macrophages and pro-inflammatory cytokines secretion, which are involved in the impairment of AT2-AT1 cells transition. Importantly, inhibition of CCL2-CCR2 axis effectively restored SWCNT-induced lung inflammation and fibrosis. In conclusion, our findings elucidate the crosstalk of lung macrophages and epithelial cells, which further regulates the progression of SWCNT-induced lung injury, and target CCL2-CCR2 axis is expected to be potential therapeutic strategy for the prevention and treatment of lung injury induced by nanoparticles.