Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease
- PMID: 32371071
- PMCID: PMC7606335
- DOI: 10.1016/j.jaci.2020.04.031
Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease
Abstract
Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD.
Objective: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD.
Methods: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence.
Results: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD.
Conclusions: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.
Keywords: 15-lipoxygenase; 15-oxo-eicosatetraenoic acid; AERD; ALOX15; CRSwNP; Chronic sinusitis; aspirin-exacerbated respiratory disease; hydroxyprostaglandin dehydrogenase; nasal polyps.
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Conflicts of Interest:
RC, DC, KH, JH, JN, CP, AS, SS, LS, DW, and KW reports no conflicts of interest. WS served on an advisory board for GlaxoSmithKline. AK reports personal fees from Astellas Pharmaceuticals. BT reports personal fees from Sanofi Regeneron/Genzyme, and OptiNose. AP reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca. LG reports personal fees from Astellas Pharmaceuticals. RK reports personal fees from Sanofi, Novartis, Lyra Pharmaceutical, and Neurent. RS reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma Inc., and Otsuka Inc. RS also has Siglec-8 and Siglec-8 ligand related patents licensed to Allakos Inc.
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Comment in
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Eicosanoid relay: Epithelial and mast cell transmetabolism in AERD.J Allergy Clin Immunol. 2021 Feb;147(2):501-503. doi: 10.1016/j.jaci.2020.12.627. J Allergy Clin Immunol. 2021. PMID: 33358894 No abstract available.
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