PT  - JOURNAL ARTICLE
AU  - Aicha Jeridi
AU  - Gizem Günes Günsel
AU  - Mariia Novikava
AU  - Sebastian Doll
AU  - Niklas J. Lang
AU  - Stijin E. Verleden
AU  - Markus Rehberg
AU  - Tobias Stoeger
AU  - Herbert B. Schiller
AU  - Marcus Conrad
AU  - Thomas M. Conlon
AU  - Ali Önder Yildirim
TI  - Ferroptosis, induced by macrophages drives COPD pathogenesis
AID  - 10.1183/23120541.LSC-2022.177
DP  - 2022 Mar 10
TA  - ERJ Open Research
PG  - 177
VI  - 8
IP  - suppl 8
4099  - http://openres.ersjournals.com/content/8/suppl_8/177.short
4100  - http://openres.ersjournals.com/content/8/suppl_8/177.full
SO  - erjor2022 Mar 10; 8
AB  - Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. It has been associated with different forms of cell death, with the number of dying epithelial cells increasing in the lungs of COPD patients. Although mainly apoptosis and necroptosis have been described to be the main types of cell death in COPD, there is increasing evidence that a recently described form of cell death called ferroptosis can be induced during the very first response to cigarette smoke (CS). GSEA revealed enrichment of ferroptosis over the other forms of cell death in COPD patients compared to non-diseased smokers and in mice exposed to CS compared to FA controls. ACSL4, a key regulator in the ferroptotic cell death pathway correlated with disease severity and was increased in COPD patients compared to non-diseased smokers. ScRNA-seq and staining of lung samples of COPD and CS-exposed mice revealed high ACSL4 expression predominantly in AT2 cells. Knowing that macrophage numbers increase after smoke exposure, we investigated the possible link between macrophages and ferroptosis induction in epithelial cells. Using in vitro approaches, we show a direct link between pro-inflammatory macrophage presence 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 but not with control or anti-inflammatory conditioned medium. Most importantly, by tracking cell death with live imaging, ferroptotic cell death could be reversed using Lip-1 but not by using zVAD or nec-1s. This study shows that macrophages can induce ferroptosis susceptibility in AT2 cells upon CS exposure.FootnotesCite this article as ERJ Open Research 2022; 8: Suppl. 8, 177.This article was presented at the 2022 ERS Lung Science Conference, in session “Poster Session 2”.This is an ERS Lung Science Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).