Eicosanoid relay: Epithelial and mast cell transmetabolism in AERD

Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a persistent sinonasal disease characterized by an outgrowth of edematous inflammatory tissue from the ethmoid sinus cavity, commonly referred to as polyps.1Stevens W.W. Schleimer R.P. Kern R.C. polyps.J Allergy Clin Immunol Pract. 2016; 4: 565-572Abstract Full Text PDF PubMed Scopus (148) Google Scholar Although mechanisms leading polyp growth are not fully understood, CRSwNP associated type 2 (T2) inflammation and asthma common comorbidity. A subset patients polyposis also exhibit hypersensitivity reactions nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase-1, such aspirin, condition aspirin-exacerbated respiratory disorder (AERD).2Kennedy J.L. Stoner A.N. Borish L. Aspirin-exacerbated disease: prevalence, diagnosis, treatment, considerations for future.Am J Rhinol Allergy. 30: 407-413Crossref (41) In addition drug reactivity, AERD often aggressive regrowth following surgical resection, sensitivity alcohol, elevated systemic levels prostaglandin D2 leukotriene (LT)E4, arachidonic acid (AA)-derived lipid mediators thought come activated mast cells (MCs). densely infiltrated eosinophils, direct targeting these pharmacologic compound dexpramipexole had little impact on scores despite achieving 94% reduction in circulating eosinophils 97% eosinophil concentration.3Laidlaw T.M. Prussin C. Panettieri R.A. Lee S. Ferguson B.J. Adappa N.D. et al.Dexpramipexole depletes blood no change size.Laryngoscope. 2019; 129: E61-E66Crossref (34) Thus, it unclear whether play pathobiologic role progression or rather recruited ongoing T2 inflammation, underscoring importance identifying other factors may drive particularly nature AERD. The epithelium exhibits strong transcriptional signature T2-associated cytokines IL-4 IL-13.4Ordovas-Montanes J. Dwyer D.F. Nyquist S.K. Buchheit K.M. Vukovic M. Deb al.Allergic memory human epithelial progenitor cells.Nature. 2018; 560: 649-654Crossref (149) Among transcripts ALOX15, encoding mediator biosynthetic enzyme arachidonate 15-lipoxygenase (15-LO). This transcript prominently upregulated mucosal diseases, including T2-high eosinophilic esophagitis.5Wenzel S.E. Tyurina Y.Y. Zhao St Croix C.M. Dar H.H. Mao G. al.PEBP1 wardens ferroptosis enabling lipoxygenase generation death signals.Cell. 2017; 171: 628-641.e26Abstract (268) Scholar,6Sherrill J.D. Kiran K.C. Blanchard Stucke E.M. Kemme K.A. Collins M.H. al.Analysis expansion esophagitis transcriptome RNA sequencing.Genes Immun. 2014; 15: 361-369Crossref (72) roles, 15-LO capable converting AA into 15-hydroperoxyeicosatetraenoic (15-HpETE), which then rapidly reduced 15-hydroxyeicosatetraenoic (15-HETE) endogenous glutathione peroxidases.7Singh N.K. Rao G.N. Emerging 12/15-lipoxygenase (ALOX15) pathologies.Prog Lipid Res. 73: 28-45Crossref (63) Depending presence enzymes, 15-HETE can act its own right mediator, be converted lipoxins through activity 5-lipoxygenase, oxidized 15-Oxo-eicosatetraenoic (15-oxo-ETE) hydroxyprostaglandin dehydrogenase (HPGD). this issue Journal Clinical Immunology, Stevens al8Stevens Staudacher A.G. Hulse K.E. Carter R.G. Winter D.R. Kato A. al.Activation pathway disease.J Immunol. 2021; 147: 600-612Abstract (13) use single-cell RNA-sequencing (scRNA-seq) conduct first comprehensive comparative evaluation metabolism CRSwNP. They power scRNA-seq simultaneously interrogate enzymes receptors leukotrienes prostaglandins across 10 identified cell populations, coming unanticipated conclusion there were few differences expression between Next, guided initial unexpected observation 15-oxo-ETE, metabolite 15-HETE, was relative CRSwNP, they shift focus ALOX15 expression. authors found primary source within significantly apical Epithelial cells, however, lacked HPGD, required convert 15-oxo-ETE. Instead, HPGD restricted polyp, many could directly adjacent 15-LO–expressing cells. Therefore, conclude 15-oxo-ETE observed likely generated via transmetabolism, generating passing nearby MCs oxidation (Fig 1). Interestingly, transmetabolic eicosanoid granulocytes platelets previously shown AERD.9Laidlaw Kidder M.S. Bhattacharyya N. Xing W. Shen Milne al.Cysteinyl overproduction driven platelet-adheren leukocytes.Blood. 2012; 119: 3790-3798Crossref (167) Granulocytes, LTA4 but LTC4, form aggregates platelets, LTC4 unable generate LTA4. These platelet-granulocyte enhanced AERD, correlate urinary LTE4 levels. whole-tissue highly those without asthma. relationship CRS polyps. further significant correlation both lifetime operations all patient groups, indicating link severity. However, noted poor detection scRNA-seq, consistent previous study polyposis.4Ordovas-Montanes Because constitutively express 15-LO7Singh protein cationic eosinophil-restricted CLC,8Stevens future studies needed determine what degree association reflects upregulation versus infiltration tissue. One major question raised authors’ findings plays progression. comment have initiated investigations determining CRS, identification would broad implications diseases. expression, intraepithelial MC hyperplasia.1Stevens Scholar,10Dougherty R.H. Sidhu S.S. Raman K. Solon Solberg O.D. Caughey G.H. al.Accumulation unique protease phenotype T(H)2-high asthma.J 2010; 125: 1046-1053.e8Abstract (176) expanded MCs, most partner conversion shared seen healthy tissue, expressing tryptase carboxypeptidase A3 chymase. any involving inflammation-associated active inflammation-driven Recently, Wenzel al5Wenzel novel potential pathobiology phosphatidylethanolamine binding protein-1 (PEBP1), expressed formed complex vitro IL-13. PEBP1/15-LO vivo conjugates 15-HpETE (PE) 15-HpETE-PE, peroxidase induces programmed known ferroptosis. Ferroptosis airway held check actions 4, converts 15-HpETE-PE 15-HETE-PE. speculated increased make sensitive barrier disruption oxidative stressors exacerbations, cigarette smoke, infections, disrupt protective effects 4. al,8Stevens integrity impaired CRSwNP,1Stevens profoundly abnormal composition.4Ordovas-Montanes possible put at risk damage response stressors. summary, al able combine measurement derivatives identify elevation originates interplay close proximity, conditions potentially present It will important how contributes or, alternately, prove useful biomarker underlying processes. Activation diseaseJournal ImmunologyVol. 147Issue 2PreviewAspirin-exacerbated (AERD) asthma, chronic (CRSwNP), intolerance medications cyclooxygenase-1. Patients more severe upper lower tract than do aspirin-tolerant dysregulation contribute Full-Text