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• W2789839986 abstract "Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology. Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology. Asthma, eosinophilic esophagitis (EoE), and chronic rhinosinusitis have become markedly more common in Western societies in the past half century. These diseases all involve end-organ dysfunction caused by persistent activation of the immune system, resulting in eosinophil-rich (type 2) immunopathology. Because these diseases cause substantial morbidity, developing new therapeutics and preventive strategies is a high priority. Such development requires an in-depth understanding of the underlying molecular and cellular mechanisms. Allergic diseases involve prominent contributions from both the innate and adaptive immune systems. Thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are generated primarily by barrier epithelial cells (EpCs) and released in the innate response to pathogens, antigens, and local injury (Fig 1). Their expression can also be persistently upregulated with severe disease, resulting in sustained pathology. Of their target cells, group 2 innate lymphoid cells (ILC2s) generate especially large quantities of type 2 cytokines (IL-5, IL-13, and IL-9)1Kabata H. Moro K. Koyasu S. Asano K. Group 2 innate lymphoid cells and asthma.Allergol Int. 2015; 64: 227-234Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 2Konya V. Mjosberg J. Lipid mediators as regulators of human ILC2 function in allergic diseases.Immunol Lett. 2016; 179: 36-42Crossref PubMed Scopus (35) Google Scholar, 3Mjosberg J. Spits H. Human innate lymphoid cells.J Allergy Clin Immunol. 2016; 138: 1265-1276Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar when stimulated with barrier-derived cytokines,4Barrett N.A. Boyce J.A. Activation of group 2 innate lymphoid cells: a new role for cysteinyl leukotrienes.J Allergy Clin Immunol. 2013; 132: 214-216Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar as do mast cells, basophils, and certain populations of TH2 cells. In mouse models of helminth infection, ILC2s are sufficient to induce mucosal eosinophilia and goblet cell hyperplasia, even in mice lacking adaptive immune systems.5Neill D.R. Wong S.H. Bellosi A. Flynn R.J. Daly M. Langford T.K.A. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (1618) Google Scholar Although less is known about the role of ILC2s in human disease, recent studies implicate ILC2s as potentially important sources of type 2 cytokines in patients with asthma, chronic rhinosinusitis, and EoE.6Jia Y. Fang X. Zhu X. Bai C. Zhu L. Jin M. et al.IL-13+ type 2 innate lymphoid cells correlate with asthma control status and treatment response.Am J Respir Cell Mol Biol. 2016; 55: 675-683Crossref PubMed Scopus (78) Google Scholar, 7Shaw J.L. Fakhri S. Citardi M.J. Porter P.C. Corry D.B. Kheradmand F. et al.IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps.Am J Respir Crit Care Med. 2013; 188: 432-439Crossref PubMed Scopus (206) Google Scholar, 8Doherty T.A. Baum R. Newbury R.O. Yang T. Dohil R. Aquino M. et al.Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.J Allergy Clin Immunol. 2015; 136: 792-794.e3Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Additionally, a population of conventional human TH2 cells identified exclusively in subjects with allergic disease display ILC2-like features (including the expression and function of receptors for TSLP, IL-33, and IL-25). These cells, termed pathogenic effector TH2 cells or “TH2A” cells have innate-like functions such that they no longer require specific antigen exposure for activation and type 2 cytokine production.9Mitson-Salazar A. Yin Y. Wansley D.L. Young M. Bolan H. Arceo S. et al.Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human TH2 cell subpopulation with enhanced function.J Allergy Clin Immunol. 2016; 137: 907-918.e9Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 10Wambre E. Bajzik V. DeLong J.H. O’Brien K. Nguyen Q.-A. Speake C. et al.A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders.Sci Transl Med. 2017; 9: eaam9171Crossref PubMed Scopus (205) Google Scholar They might account for the majority of cytokine-producing T cells in patients with allergic disease. Thus the mechanisms that control innate and adaptive lymphoid effectors, both positively and negatively, carry not only pathobiological significance but also potential therapeutic implications, especially in patients with severe disease. Lipid mediators derived from arachidonic acid (AA) play substantial roles in the control of ILC2 and TH2 cell function. AA is stored in membrane phospholipids and released at high levels on cell activation. AA is metabolized to prostaglandins (PGs), leukotrienes (LTs), and other bioactive mediators through specific synthetic enzyme pathways.2Konya V. Mjosberg J. Lipid mediators as regulators of human ILC2 function in allergic diseases.Immunol Lett. 2016; 179: 36-42Crossref PubMed Scopus (35) Google Scholar, 11Beermann C. Neumann S. Fubroich D. Zielen S. Schubert R. Combinations of distinct long-chain polyunsaturated fatty acid species for improved dietary treatment against allergic bronchial asthma.Nutrition. 2016; 32: 1165-1170Crossref PubMed Scopus (16) Google Scholar AA-derived bioactive lipids have receptor-specific inductive and suppressive effects that can influence the duration and magnitude of the immunopathology and end-organ dysfunction. This carries the potential for lipid mediator–targeted therapies to substantially affect allergic diseases.12Hayashi M. Koya T. Kawakami H. Sakagami T. Hasegawa T. Kagamu H. et al.A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice: Original article/Experimental models of allergic disease.Clin Exp Allergy. 2010; 40: 317-326Crossref PubMed Scopus (13) Google Scholar, 13Israel E. Cohn J. Dubé L. Drazen J.M. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group.JAMA. 1996; 275: 931-936Crossref PubMed Google Scholar, 14Israel E. Chervinsky P.S. Friedman B. Van Bavel J. Skalky C.S. Ghannam A.F. et al.Effects of montelukast and beclomethasone on airway function and asthma control.J Allergy Clin Immunol. 2002; 110: 847-854Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 15Shin I.S. Jeon W.Y. Shin H.K. Lee M.Y. Effects of montelukast on subepithelial/peribronchial fibrosis in a murine model of ovalbumin induced chronic asthma.Int Immunopharmacol. 2013; 17: 867-873Google Scholar This review will cover our current understanding of the proinflammatory and anti-inflammatory functions of AA-derived lipids, their cells of origin, and their receptors. Although many cell types (including mast cells, basophils, and eosinophils) relevant to type 2 immunopathology express these receptors, we will focus primarily on the effects of lipid mediators on ILC2s and TH2 cells, as well as their upstream cytokine sources, where applicable, because of the recent increase in published literature on this subject. LTs are 5-lipoxygenase (5-LO)–derived AA products. 5-LO, while anchored to a membrane-anchored 5-LO–activating protein, oxidizes AA to generate 5-hydroxyperoxyeicosatetraenoic acid and then to generate 5-hydroxytetraenoic acid (5-HETE). 5-LO further dehydrates 5-HETE to LTA4, an unstable intermediate.16Peters-Golden M. Henderson W.R. Leukotrienes.N Engl J Med. 2007; 357: 1841-1854Crossref PubMed Scopus (883) Google Scholar Neutrophils hydrolyze LTA4 to LTB4 through a cytosolic LTA4 hydrolase enzyme, whereas eosinophils and basophils conjugate LTA4 to reduced glutathione by leukotriene C4 synthase (LTC4S) to form LTC4, the parent of the cysteinyl leukotrienes (cysLTs). Mast cells and macrophages express both terminal enzymes, although both cell types tend to generate LTC4 in excess of LTB4. Platelets lack 5-LO or 5-LO–activating protein and cannot generate LTA4 but do express LTC4S and can convert excess granulocyte-derived LTA4 to LTC4, thus increasing cysLT levels with inflammation. LTC4 is exported to the extracellular space, where it is converted first to LTD4 through enzymatic removal of glutamic acid from the glutathione adduct and then rapidly to the stable end-metabolite LTE4 through glycine removal.16Peters-Golden M. Henderson W.R. Leukotrienes.N Engl J Med. 2007; 357: 1841-1854Crossref PubMed Scopus (883) Google Scholar LTE4 is excreted unchanged in urine. The stability of LTE4 and instability of LTD4 account for the typical rank order concentrations of LTE4 > LTC4 >> LTD4 in extracellular fluids (Fig 2). LTC4, LTD4, and LTE4 have varied potencies and sites of action caused by the existence of at least 3 different receptors, termed cysteinyl leukotriene receptor type 1 (CysLT1R), cysteinyl leukotriene receptor type 2 (CysLT2R), and cysteinyl leukotriene receptor type 3 (CysLT3R). CysLT1R is a high-affinity LTD4 receptor,17Lynch K.R. O'Neill G.P. Liu Q. Im D.S. Sawyer N. Metters K.M. et al.Characterization of the human cysteinyl leukotriene CysLT1 receptor.Nature. 1999; 399: 789-793Crossref PubMed Scopus (885) Google Scholar, 18Martin V. Sawyer N. Stocco R. Unett D. Lerner M.R. Abramovitz M. et al.Molecular cloning and functional characterization of murine cysteinyl-leukotriene 1 (CysLT 1) receptors.Biochem Pharmacol. 2001; 62: 1193-1200Crossref PubMed Scopus (40) Google Scholar, 19Sarau H.M. Ames R.S. Chambers J. Ellis C. Elshourbagy N. Foley J.J. et al.Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor.Mol Pharmacol. 1999; 56: 657-663Crossref PubMed Scopus (304) Google Scholar whereas CysLT2R binds to LTD4 and LTC4 with equal avidity.20Nothacker H.-P. Wang Z. Zhu Y. Reinscheid R.K. Lin S.H.S. Civelli O. Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist.Mol Pharmacol. 2000; 58: 1601-1608Crossref PubMed Scopus (163) Google Scholar, 21Takasaki J. Kamohara M. Matsumoto M. Saito T. Sugimoto T. Ohishi T. et al.The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor.Biochem Biophys Res Commun. 2000; 274: 316-322Crossref PubMed Scopus (176) Google Scholar CysLT3R (previously known as GPR99) preferentially binds LTE4.22Kanaoka Y. Maekawa A. Austen K.F. Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand.J Biol Chem. 2013; 288: 10967-10972Crossref PubMed Scopus (138) Google Scholar, 23Bankova L.G. Lai J. Yoshimoto E. Boyce J.A. Austen K.F. Kanaoka Y. et al.Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99.Proc Natl Acad Sci U S A. 2016; 113: 6242-6247Crossref PubMed Scopus (77) Google Scholar Studies with selective antagonists verified that cysLTs acting at CysLT1R account for a substantial fraction of the bronchoconstriction on inhalational allergen challenge in atopic asthmatic patients and that cysLTs participate in asthma exacerbations.24Sekioka T. Kadode M. Fujii M. Kawabata K. Abe T. Horiba M. et al.Expression of CysLT2 receptors in asthma lung, and their possible role in bronchoconstriction.Allergol Int. 2015; 64: 351-358Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 25Shirasaki H. Himi T. Role of cysteinyl leukotrienes in allergic rhinitis.Adv Otorhinolaryngol. 2016; 77: 40-45PubMed Google Scholar To date, the lack of clinically available antagonists has precluded a systematic examination of the roles of CysLT2R and GPR99/CysLT3R in human subjects. Studies in transgenic mice (see below) demonstrate that each cysLT receptor has a unique set of functions and cellular targets in the induction and amplification of type 2 immunopathology (Table I).Table ILipid mediator receptors and their cellular expression: Outline of various cell types known to express lipid mediator receptorsReceptor(s)Lipid mediatorCell typesMouseHumanCysLT1R = CysLT2RLTC4ILC2s, DCs, platelets, mast cells, endothelial cellsEpCs, bronchial smooth muscle, mast cells, macrophages, cardiac Purkinje cells, endothelial cellsCysLT1R >>> CysLT2RLTD4ILC2s, TH2 cells, DCs, platelets, EpCsILC2s, TH2 cells, EpCs, bronchial smooth muscle, mast cells, macrophagesCysLT3RLTE4Airway EpCsVascular smooth muscle cellsDP1PGD2Langerhans cells, DCs, mast cellsMicroglia, astrocytes, endothelial cells, platelets, DCs, mast cells, eosinophils, basophils and T cells, alveolar macrophagesCRTH2/DP2TH2 cells, eosinophils, basophils, T cellsEosinophils, basophils, ILC2s, TH2 cells, peTH2 cells, mast cells, alveolar macrophagesEP1PGE2MacrophagesEP2DCs, T cells, mast cells, eosinophils, macrophagesMast cells, eosinophils, neutrophils, T cells, DCs, ILC2s, fibroblastsEP3Mast cells, eosinophils, macrophagesEosinophilsEP4DCs, T cells, ILC3s, mast cells, eosinophils, macrophagesILC3s, mast cells, eosinophils, T cells, DCs, cutaneous Langerhans cells, ILC2s, airway smooth muscleIPPGI2DCs, ILC2s, CD4+ T cells, TH2 cells, eosinophilsDCs, ILC2sALX/FPRLXsILC2s, NK cellsNK, Natural killer; peTH2, pathogenic effector TH2. Open table in a new tab NK, Natural killer; peTH2, pathogenic effector TH2. Patients with spontaneous asthma exacerbations have high urinary LTE4 levels relative to their baseline values. Both the 5-LO inhibitor zileuton and selective CysLT1R antagonists provide significant protection from asthma exacerbations in controlled trials, verifying the contribution of cysLTs to asthma exacerbations.13Israel E. Cohn J. Dubé L. Drazen J.M. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group.JAMA. 1996; 275: 931-936Crossref PubMed Google Scholar, 14Israel E. Chervinsky P.S. Friedman B. Van Bavel J. Skalky C.S. Ghannam A.F. et al.Effects of montelukast and beclomethasone on airway function and asthma control.J Allergy Clin Immunol. 2002; 110: 847-854Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 26Drazen J.M. O’Brien J. Sparrow D. Weiss S.T. Martins M.A. Israel E. et al.Recovery of leukotriene E4 from the urine of patients with airway obstruction.Am Rev Respir Dis. 1992; 146: 104-108Crossref PubMed Scopus (174) Google Scholar Baseline levels of urinary LTE4 are significantly increased in obese asthmatic patients than in nonobese asthmatic patients.27Giouleka P. Papatheodorou G. Lyberopoulos P. Karakatsani A. Alchanatis M. Roussos C. et al.Body mass index is associated with leukotriene inflammation in asthmatics.Eur J Clin Invest. 2011; 41: 30-38Crossref PubMed Scopus (47) Google Scholar In preschool children increased urinary LTE4 levels correlate with high serum IgE levels and strongly predict subsequent asthma development.28Chiu C.Y. Tsai M.H. Yao T.C. Tu Y.L. Hua M.C. Yeh K.W. et al.Urinary LTE4 levels as a diagnostic marker for IgE-mediated asthma in preschool children: a birth cohort study.PLoS One. 2014; 9: 1-12Google Scholar The early observations that inhaled LTE4 induced eosinophil accumulation in the bronchial mucosa of patients with mild asthma were the first evidence that cysLTs promote type 2 immunity.29Laitinen L.A. Haahtela T. Vilkka V. Lee T.H. Spur B.W. Leukotriene E4 and granulocytic infiltration into asthmatic airways.Lancet. 1993; 341: 989-990Abstract PubMed Scopus (485) Google Scholar Administration of zileuton or montelukast (CysLT1R inhibitor) reduce blood eosinophil counts.30Price D.B. Hernandez D. Magyar P. Fiterman J. Beeh K.M. James I.G. et al.Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma.Thorax. 2003; 58: 211-216Crossref PubMed Scopus (208) Google Scholar, 31Dahlén S.-E. Malmström K. Nizankowska E. Dahlén B. Kuna P. Kowalski M. et al.Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial.Am J Respir Crit Care Med. 2002; 165: 9-14Crossref PubMed Scopus (292) Google Scholar, 32Busse W. Kraft M. Cysteinyl leukotrienes in allergic inflammation.Chest. 2005; 127: 1312-1326PubMed Scopus (0) Google Scholar In patients with aspirin-exacerbated respiratory disease (AERD), cysLT overproduction is accompanied by severe asthma and chronic eosinophilic rhinosinusitis. The symptomatic improvement afforded these patients by cysLT-targeted drugs is consistent with the role of cysLTs as inducers and amplifiers of type 2 immunopathology in human subjects, especially those with AERD (Fig 2).31Dahlén S.-E. Malmström K. Nizankowska E. Dahlén B. Kuna P. Kowalski M. et al.Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial.Am J Respir Crit Care Med. 2002; 165: 9-14Crossref PubMed Scopus (292) Google Scholar, 33Dahlén B. Nizankowska E. Szczeklik A. Zetterström O. Bochenek G. Kumlin M. et al.Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics.Am J Respir Crit Care Med. 1998; 157: 1187-1194Crossref PubMed Scopus (349) Google Scholar, 34Dahlén B. Treatment of aspirin-intolerant asthma with antileukotrienes.Am J Respir Crit Care Med. 2000; 161: 137-141Crossref PubMed Scopus (37) Google Scholar Human TH2 cells, but not TH1 cells, express CysLT1R, and their stimulation with cysLTs elicited IL-13 production.4Barrett N.A. Boyce J.A. Activation of group 2 innate lymphoid cells: a new role for cysteinyl leukotrienes.J Allergy Clin Immunol. 2013; 132: 214-216Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 35Karta M.R. Broide D.H. Doherty T.A. Insights into group 2 innate lymphoid cells in human airway disease.Curr Allergy Asthma Rep. 2016; 16: 8Crossref PubMed Scopus (56) Google Scholar Curiously, although the response is completely blocked by CysLT1R antagonists, LTE4 is more potent than LTD4 for this effect. In addition, the effect of LTE4 on human TH2 cells is amplified by PGD2, which acts synergistically with LTE4 to induce not only TH2 cytokines but also IL-22, IL-8, and GM-CSF.36Xue L. Fergusson J. Salimi M. Panse I. Ussher J.E. Hegazy A.N. et al.Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk.J Allergy Clin Immunol. 2015; 135: 1358-1366.e11Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Human ILC2s also express CysLT1R, and this expression is greater in cells from atopic subjects compared with nonatopic control subjects. Isolated human ILC2s showed induced migration, survival, and type 2 cytokine production on ex vivo stimulation with LTE4 to a greater extent than with LTD4.37Salimi M. Stöger L. Liu W. Go S. Pavord I. Klenerman P. et al.Cysteinyl leukotriene E 4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D 2 and epithelial cytokines.J Allergy Clin Immunol. 2017; 140: 1090-1100.e11Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Furthermore, as is the case for human TH2 cells, LTE4 and PGD2 have synergistic effects with IL-25, IL-33, and TSLP on ILC2s in vitro to enhance type 2 cytokine production. Mouse lung ILC2s proliferate and generate IL-4, IL-13, and IL-5 in response to exogenous LTC4 and LTD4, which can be blocked by CysLT1R antagonists and is absent in mice lacking CysLT1R.38Doherty T.A. Khorram N. Lund S. Mehta A.K. Croft M. Broide D.H. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar LTC4 and LTD4 also synergize with IL-33 to promote TH2 cytokine generation.39von Moltke J. O’Leary C.E. Barrett N.A. Kanaoka Y. Austen K.F. Locksley R.M. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.J Exp Med. 2017; 214: 27-37Crossref PubMed Scopus (102) Google Scholar, 40Lund S.J. Portillo A. Cavagnero K. Baum R.E. Naji L.H. Badrani J.H. et al.Leukotriene C4 potentiates IL-33–induced group 2 innate lymphoid cell activation and lung inflammation.J Immunol. 2017; 199: 1096-1104Crossref PubMed Scopus (76) Google Scholar Notably, although LTC4, LTD4, and LTE4 can all expand and activate lung ILC2s in mice, the effects of LTE4 appeared to be indirect and (unlike human ILC2s) independent of CysLT1R.39von Moltke J. O’Leary C.E. Barrett N.A. Kanaoka Y. Austen K.F. Locksley R.M. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.J Exp Med. 2017; 214: 27-37Crossref PubMed Scopus (102) Google Scholar, 41Liu T. Barrett N.A. Kanaoka Y. Yoshimoto E. Garofalo D. Cirka H. et al.Type 2 cysteinyl leukotriene receptors drive IL-33-dependent type 2 immunopathology and aspirin sensitivity.J Immunol. 2018; 200: 915-927Crossref PubMed Scopus (42) Google Scholar These studies support a role for cysLTs in amplifying inflammation in type 2 immunity by acting at both the innate and adaptive lymphocyte compartments. Human nasal EpCs express both CysLT1R and CysLT2R based on immunostaining of mucosal biopsy specimens.42Corrigan C. Mallett K. Ying S. Roberts D. Parikh A. Scadding G. et al.Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis.J Allergy Clin Immunol. 2005; 115: 316-322Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Although studies examining the role of cysLTs in EpC function are sparse, CysLT1R signaling conferred protection from epithelial damage in a model of airway injury induced by (Cl2)-elicited oxidative stress.43McGovern T. Goldberger M. Chen M. Allard B. Hamamoto Y. Kanaoka Y. et al.CysLT1 receptor is protective against oxidative stress in a model of irritant-induced asthma.J Immunol. 2016; 197: 266-277Crossref PubMed Scopus (17) Google Scholar CysLT3R/GPR99 is expressed dominantly by murine respiratory EpCs. Intranasal administration of LTE4 to wild-type (WT) mice elicited mucin release by goblet cells, which was abrogated in CysLT3R-null mice. Endogenous CysLTs-GPR99 signaling was also crucial for Alternaria alternata–induced mucin release.23Bankova L.G. Lai J. Yoshimoto E. Boyce J.A. Austen K.F. Kanaoka Y. et al.Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99.Proc Natl Acad Sci U S A. 2016; 113: 6242-6247Crossref PubMed Scopus (77) Google Scholar Additionally, lung EpC-derived IL-33 is sharply increased in Dermatophagoides farinae extract (Df)-treated microsomal PGE2 synthase (Ptges) null mice, which show strong cysLT-driven type 2 pathology relative to WT control mice. The increase in IL-33 levels was abrogated in LTC4S-null mice, which was attributable to endogenous cysLT signaling through CysLT2R.41Liu T. Barrett N.A. Kanaoka Y. Yoshimoto E. Garofalo D. Cirka H. et al.Type 2 cysteinyl leukotriene receptors drive IL-33-dependent type 2 immunopathology and aspirin sensitivity.J Immunol. 2018; 200: 915-927Crossref PubMed Scopus (42) Google Scholar, 44Liu T. 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COX-1 accounts for constitutive PG generation in most cell types, whereas COX-2 expression can be induced or upregulated in response to signaling through exogenous (eg, endotoxin) and endogenous (eg, IL-1) danger signals. Such stimuli sharply increase PG production, which reflects COX-2 function. PGH2 serves as a substrate for conversion to one of 5 different terminal PGs (PGD2, PGE2, PGF2, PGI2, and thromboxane [TX] A2, respectively) by corresponding PG synthases. Mast cells express both hematopoietic prostaglandin D synthase (hPGDS) and TXA2 synthase and can generate PGD2 and smaller amounts of TXA2.45Boyce J.A. The role of mast cells in asthma.Prostaglandins Leukot Essent Fat Acids. 2003; 69: 195-205Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 46Laidlaw T.M. Boyce J.A. Pathogenesis of aspirin-exacerbated respiratory disease and reactions.Immunol Allergy Clin North Am. 2013; 33: 195-210Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Platelets also express both hPGDS and TXA2 synthase, although TXA2 is their primary COX product.47Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3030) Google Scholar EpCs, fibroblasts, and macrophages generate PGE2 because of their expressions of microsomal prostaglandin E2 synthase 1 (mPGES-1), the most dominant of 3 enzymes capable of catalyzing the formation of PGE2.46Laidlaw T.M. Boyce J.A. Pathogenesis of aspirin-exacerbated respiratory disease and reactions.Immunol Allergy Clin North Am. 2013; 33: 195-210Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 48Duan Y. Chen F. Zhang A. Zhu B. Sun J. Xie Q. et al.Aspirin inhibits lipopolysaccharide-induced COX-2 expression and PGE2 production in porcine alveolar macrophages by modulating protein kinase C and protein tyrosine phosphatase activity.BMB Rep. 2014; 47: 45-50Crossref PubMed Scopus (16) Google Scholar, 49Samuchiwal S.K. Balestrieri B. Raff H. Boyce J.A. Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cyclic cAMP-EPAC-dependent pathway.J Biol Chem. 2017; 292: 8195-8206Crossref PubMed Scopus (28) Google Scholar PGI2 synthase is expressed prominently by endothelial cells and follicular dendritic cells (DCs), which generate PGI2 (also known as prostacyclin) as their dominant COX pathway product. Finally, the human PGF synthase enzyme is expressed primarily in lungs, where it catalyzes 2 reactions: formation of PGF2α from PGH2 and conversion of PGD2 to 9α, 11β-PGF, which is a potent bronchoconstrictor.50Beasley R. Varley J. Robinson C. Holgate S.T. 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Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3030) Google Scholar PGD2 signals directly through 2 G protein–coupled receptors (GPCRs) termed D prostanoid (DP)1 and DP2, respectively, or chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2).52Pettipher R. The roles of the prostaglandin D(2) receptors DP(1) and CRTH2 in promoting allergic responses.Br J Pharmacol. 2008; 153: S191-S199PubMed Google Scholar DP1 receptors are homologous to other PG-responsive GPCRs, signal through stimulatory G p" @default.
• W2789839986 created "2018-03-29" @default.
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• W2789839986 date "2018-04-01" @default.
• W2789839986 modified "2023-10-17" @default.
• W2789839986 title "Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology" @default.
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