COPD pathogenesis is dependent on ferroptotic death of AT2 cells driven by pro-inflammatory Macrophages

COPD has been associated with different forms of cell death including apoptosis and necroptosis. Cell death affects both epithelial and endothelial cells and was shown to be increased in the lungs of COPD patients. Although mainly apoptosis and necroptosis have been described to be the main responsible types of cell death in COPD, there is increasing evidence that a recently described form of cell death called ferroptosis can be induced upon CS exposure. When comparing COPD patients to non-diseased smokers, the Gene set enrichment analysis (GSEA) revealed a clear enrichment of ferroptosis over the other forms of cell death. Similar results were achieved when comparing mice exposed to CS to the FA controls. Particular genes have been shown to dictates ferroptosis sensitivity to cells. ACSL4 (Acyl-CoA-Synthetase Long Chain Family Member 4), is a critical determinant of ferroptosis sensitivity, since it shapes the cellular lipid composition in cells. Interestingly, it was increased in COPD patients compared to non-diseased smokers and correlated with disease severity. scRNA-seq and staining of lung samples of COPD and CS-exposed mice revealed high ACSL4 expression in AT2 cells. Further, we could show a direct link between presence of M1 macrophages in smoked lungs and ferroptotic cell death occurrence in AT2 cells. We detected Lipidperoxidation and ACSl4 upregulation in AT2 cells treated with conditioned medium of pro-inflammatory macrophages. By tracking cell death with live imaging, ferroptotic cell death could be reversed using the specific ferroptosis-inhibitor Liproxstatin-1 but could not prevented using apoptosis- or necroptosis inhibitors.