Loss of apolipoprotein E contributes to inflammatory macrophage activation and ferroptosis in NSAID-exacerbated respiratory disease.

Abstract

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is characterized by chronic asthma, nasal polyposis, and intolerance of nonsteroidal anti-inflammatory drugs. We recently described aberrant macrophage activation and lipid metabolism in N-ERD; however, local drivers of nasal inflammation in N-ERD are incompletely understood. Our aim was to study how apolipoprotein E (ApoE) deficiency in the N-ERD nasal mucosa affects the cross talk and inflammatory activation of macrophages and epithelial cells. We combined transcriptional and mediator analysis of samples from patients with N-ERD and primary human cell culture to study ApoE in epithelial and myeloid cells. Nasal scrapings from patients with N-ERD exhibited decreased APOE expression compared with that exhibited by nasal mucosa of healthy individuals, but APOE was inherently low in epithelial cells. Instead, myeloid cells expressed highly abundant APOE, which was reduced in monocyte-derived macrophages from patients with N-ERD. Small interfering RNA-mediated knockdown of APOE in monocyte-derived macrophages resulted in increased expression of CXCL7, an inflammatory chemokine implicated in N-ERD. In addition, highly oxidized arachidonyl-phosphatidylethanolamine accumulated in APOE-knockdown macrophages, and ApoE protected macrophages from ferroptotic cell death. Our results suggest a role for myeloid ApoE in regulating the cross talk between macrophages and epithelial cells, as well as in ferroptosis during type 2 airway inflammation. ApoE deficiency may thus contribute to chronic type 2 inflammation in patients with N-ERD, and its restoration could help reestablish normal epithelial barrier integrity and macrophage effector functions.