LCCPs exposure induces pulmonary inflammatory injury via AIM2 mediated pulmonary macrophage PANoptosis and M1 polarization

Abstract

In recent years, with the wide application of long-chain chlorinated paraffins (LCCPs), long-chain chlorinated paraffins have been detected all over the world. High concentrations of LCCPs are being detected in the air of human living environments. As the main gas exchange organ of the human body, the lungs are responsible for transporting oxygen throughout the body, but there are no studies on the toxicological effects of LCCPs on the lungs. In this study, in vitro and in vivo models were used to investigate the toxicological damage of LCCPs to the lungs and its potential mechanism. In vitro, this study found that LCCPs induced mitochondrial damage and oxidative stress in alveolar epithelial cells (AECs) and alveolar macrophages (AMs), and promoted apoptosis in AECs as well as PANoptosis in AMs. Molecular mechanism studies have revealed that mtDNA leakage into the cytoplasm through VDAC protein channels activated AIM2 to assemble inflammasomes, which in turn triggered the cellular innate immune response. At the same time, AIM2 activation triggered a macrophage phenotype towards pro-inflammatory (M1) polarization, reducing macrophage phagocytosis and repair. In vivo, alveolar macrophages were found to be the key regulators of LCCPs-induced pneumonia, and the upregulation of AIM2 led to the secretion of pro-inflammatory cytokines by alveolar macrophages, which recruited neutrophils to the alveoli, along with the loss of their ability to clear dead cells and to repair tissue damage. The pro-inflammatory response of macrophages exacerbates the alveolar homeostatic imbalance, ultimately leading to AIM2-dependent lung inflammation. The results of this study indicate that LCCPs may have a harmful effect in promoting pneumonia, suggesting that humans need to control the use of LCCPs in the future.