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

Gilles Schmiz; Pascal Haimerl; Isika Ram; Manuel Kulagin; Benedikt Spitzlberger; Fiona D R Henkel; Franziska Hartung; Sonja Schindela; Zhigang Rao; Andreas Koeberle; Carsten B Schmidt-Weber; Adam M Chaker; Antonie Lechner; Julia Esser-von Bieren

doi:10.1016/j.jaci.2025.06.010

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

J Allergy Clin Immunol. 2025 Jun 19:S0091-6749(25)00652-9. doi: 10.1016/j.jaci.2025.06.010. Online ahead of print.

Affiliations

¹ Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, 80802 Munich, Germany.
² Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland.
³ Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
⁴ Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria; Institute of Pharmaceutical Sciences and Excellence Field BioHealth, University of Graz, 8010 Graz, Austria.
⁵ Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, 80802 Munich, Germany; Department of Otorhinolaryngology and Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany.
⁶ Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, 80802 Munich, Germany. Electronic address: toni.lechnerfriedl@uzh.ch.
⁷ Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, 80802 Munich, Germany; Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: julia.esser-vonbieren@unil.ch.

PMID: 40543901
DOI: 10.1016/j.jaci.2025.06.010

Abstract

Background: NSAID-exacerbated respiratory disease (N-ERD) is characterized by chronic asthma, nasal polyposis and intolerance to nonsteroidal anti-inflammatory drugs. We have recently described aberrant macrophage activation and lipid metabolism in N-ERD, however local drivers of nasal inflammation in N-ERD are incompletely understood.

Objective: To study how apolipoprotein E deficiency in the N-ERD nasal mucosa affects the crosstalk and inflammatory activation of macrophages and epithelial cells.

Methods: We combined transcriptional and mediator analysis of N-ERD patient samples and primary human cell culture to study ApoE in epithelial and myeloid cells.

Results: N-ERD nasal scrapings exhibited decreased APOE expression in comparison to healthy nasal mucosa, but APOE was inherently low in epithelial cells. Instead, myeloid cells expressed highly abundant APOE, which was reduced in monocyte-derived macrophages from N-ERD patients. siRNA-mediated knockdown of APOE in monocyte-derived macrophages resulted in increased CXCL7 expression, 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.

Conclusion: Our results suggest a role for myeloid ApoE in regulating the crosstalk between macrophages and epithelial cells as well as ferroptosis during type 2 airway inflammation. ApoE deficiency may thus contribute to chronic type 2 inflammation in N-ERD, and its restoration could help reestablish normal epithelial barrier integrity and macrophage effector functions.

Keywords: Apolipoprotein; Ferroptosis; Innate immunity; Macrophage; Mucosal immunology; NSAID-exacerbated respiratory disease.