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 aspirintolerant 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 (103 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 5 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 1 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. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

Adult‐onset eosinophilic airway diseases

“…A missense variant in ALOX15 (p.Thr560Met), resulting in near total loss of 15‐lipoxygenase activity, showed the largest protective effects against the risk of both NP and CRS. A recent study using single‐cell RNA sequencing has shown that ALOX15 was predominantly expressed by apical epithelial cells and significantly increased in NPs of N‐ERD patients compared to NPs of CRSwNP patients 44 . The expression levels significantly correlated with sinus disease severity and were associated with the presence of asthma.…”

“…The expression levels significantly correlated with sinus disease severity and were associated with the presence of asthma. 44 A downstream product of 15‐lipoxygenase (15‐oxo‐ETE) was elevated in NP compared with that in healthy sinonasal tissue, and these findings suggest the involvement and interactions of epithelial and mast cells in the transmetabolic process 44 . IL‐13 further contributes to tissue eosinophilia through eotaxin‐3 production from fibroblasts and epithelial cells, 45 reportedly in a 15‐lipoxygenase‐1‐dependent manner 46 …”

“…epithelial cells and significantly increased in NPs of N-ERD patients compared to NPs of CRSwNP patients 44. The expression levels significantly correlated with sinus disease severity and were associated with the presence of asthma 44. A downstream product of 15-lipoxygenase (15-oxo-ETE) was elevated in NP compared with that in healthy sinonasal tissue, and these findings suggest the involvement and interactions of epithelial and mast cells in the transmetabolic process.…”

“…epithelial cells and significantly increased in NPs of N-ERD patients compared to NPs of CRSwNP patients 44. The expression levels significantly correlated with sinus disease severity and were associated with the presence of asthma 44.…”

<p>The Role of Mast Cells in Aspirin-Exacerbated Respiratory Disease (AERD) Pathogenesis: Implications for Future Therapeutics</p>

“…A novel mediator, 15-oxo-ETE was also recently identified in AERD that is a product of the 15-lipoxygenase pathway. 26 MCs appear to be critical in this process using MC-derived hematopoietic PGD2 synthase (HPGDS) to generate 15-oxo-ETE.…”