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• W1977758373 abstract "The pathology of allergic inflammation in patients with asthma and allergic gastrointestinal disease is dominated by eosinophil infiltration and the local generation of a characteristic cassette of cytokines (IL-4, IL-5, and IL-13).1Foster P.S. Martinez-Moczygemba M. Huston D.P. Corry D.B. Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease.Pharmacol Ther. 2002; 94: 253-264Crossref PubMed Scopus (69) Google Scholar Although these cytokines can be generated by TH2 cells, studies in both human subjects2Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (884) Google Scholar and rodents3Voehringer D. Reese T.A. Huang X. Shinkai K. Locksley R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.J Exp Med. 2006; 203: 1435-1446Crossref PubMed Scopus (260) Google Scholar, 4Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar, 5Hurst S.D. Muchamuel T. Gorman D.M. Gilbert J.M. Clifford T. Kwan S. et al.New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25.J Immunol. 2002; 169: 443-453Crossref PubMed Scopus (526) Google Scholar have implicated innate cell sources of the same cytokines. In 2010, several laboratories simultaneously reported novel innate lymphoid cells in the mesenteric fat and gut-associated lymphoid tissues that expanded and generated IL-5 and IL-13 in vivo in response to exogenous IL-25 and IL-33 or to helminth infection.6Neill D.R. Wong S.H. Bellosi A. Flynn R.J. Daly M. Langford T.K. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (1592) Google Scholar, 7Saenz S.A. Siracusa M.C. Perrigoue J.G. Spencer S.P. Urban Jr., J.F. Tocker J.E. et al.IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.Nature. 2010; 464: 1362-1366Crossref PubMed Scopus (470) Google Scholar, 8Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. et al.Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.Nature. 2010; 463: 540-544Crossref PubMed Scopus (1477) Google Scholar A similar population was later found in mouse liver, spleen, and lung tissue.9Price A.E. Liang H.E. Sullivan B.M. Reinhardt R.L. Eisley C.J. Erle D.J. et al.Systemically dispersed innate IL-13-expressing cells in type 2 immunity.Proc Natl Acad Sci U S A. 2010; 107: 11489-11494Crossref PubMed Scopus (878) Google Scholar, 10Halim T.Y. Krauss R.H. Sun A.C. Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation.Immunity. 2012; 36: 451-463Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar As such, these studies suggested that cells of the innate immune system could potentially initiate or amplify eosinophilic inflammation at mucosal sites in response to stimuli, such as tissue injury, viral infection, or pathogen-associated molecular patterns, without the requirement for antigen specificity. Shortly thereafter, a cell population with similar characteristics was identified in human intestine, lung, and nasal polyp tissue that expresses CRTH2, the chemoattractant receptor for prostaglandin D2.2Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (884) Google Scholar A recent consensus has reclassified these cells in both mice and human subjects as group 2 innate lymphoid cells (ILC2s).11Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1709) Google ScholarILC2s arise from a common lymphoid progenitor that expresses the transcriptional repressor inhibitor of DNA binding 2. They are related to group 1 innate lymphoid cells (ILC1s; which include natural killer cells and IFN-γ–generating ILC1s) and group 3 innate lymphoid cells (which generate IL-17 and IL-22). Although ILC2s share the developmental requirement for IL-7 and IL-2 with ILC1s and group 3 innate lymphoid cells, they differ from these other innate lymphoid cells in their expression of retinoic acid receptor–related orphan receptor α and GATA3, a transcription factor also linked to the development of conventional TH2 cells.12Mjosberg J. Bernink J. Golebski K. Karrich J.J. Peters C.P. Blom B. et al.The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells.Immunity. 2012; 37: 649-659Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 13Halim T.Y. MacLaren A. Romanish M.T. Gold M.J. McNagny K.M. Takei F. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation.Immunity. 2012; 37: 463-474Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar The role of ILC2s in human disease is speculative at this stage; however, mouse models suggest that this cell population might provide effector cytokines at levels sufficient to eliminate helminths,8Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. et al.Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.Nature. 2010; 463: 540-544Crossref PubMed Scopus (1477) Google Scholar amplify antigen-induced airway hyperreactivity,14Barlow J.L. Bellosi A. Hardman C.S. Drynan L.F. Wong S.H. Cruickshank J.P. et al.Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity.J Allergy Clin Immunol. 2012; 129: 191-198Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar trigger eosinophilic pulmonary inflammation, and promote both airway hyperreactivity and tissue healing after influenza virus infection.15Chang Y.J. Kim H.Y. Albacker L.A. Baumgarth N. McKenzie A.N. Smith D.E. et al.Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity.Nat Immunol. 2011; 12: 631-638Crossref PubMed Scopus (629) Google Scholar, 16Monticelli L.A. Sonnenberg G.F. Abt M.C. Alenghat T. Ziegler C.G. Doering T.A. et al.Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.Nat Immunol. 2011; 12: 1045-1054Crossref PubMed Scopus (1082) Google Scholar In each instance their activation is thought to occur principally through IL-33, IL-25, and/or thymic stromal lymphopoietin generated by the perturbed barrier cells.Cysteinyl leukotrienes (CysLTs) are arachidonic acid–derived lipid mediators and the most potent known constrictors of smooth muscle.17Weiss J.W. Drazen J.M. McFadden Jr., E.R. Weller P.F. Corey E.J. Lewis R.A. et al.Comparative bronchoconstrictor effects of histamine, leukotriene C, and leukotriene D in normal human volunteers.Trans Assoc Am Physicians. 1982; 95: 30-35PubMed Google Scholar Leukotriene (LT) C4, the parent CysLT, is generated through the 5-lipoxygenase and LTC4 synthase pathway18Reid G.K. Kargman S. Vickers P.J. Mancini J.A. Leveille C. Ethier D. et al.Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis.J Biol Chem. 1990; 265: 19818-19823Abstract Full Text PDF PubMed Google Scholar, 19Lam B.K. Penrose J.F. Freeman G.J. Austen K.F. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4.Proc Natl Acad Sci U S A. 1994; 91: 7663-7667Crossref PubMed Scopus (247) Google Scholar in activated hematopoietic cells, including eosinophils, mast cells, basophils, macrophages, myeloid dendritic cells, and platelet-granulocyte complexes.20Boyce J.A. Lam B.K. Penrose J.F. Friend D.S. Parsons S. Owen W.F. et al.Expression of LTC4 synthase during the development of eosinophils in vitro from cord blood progenitors.Blood. 1996; 88: 4338-4347Crossref PubMed Google Scholar, 21Hsieh F.H. Lam B.K. Penrose J.F. Austen K.F. Boyce J.A. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4.J Exp Med. 2001; 193: 123-133Crossref PubMed Scopus (180) Google Scholar, 22Laidlaw T.M. Kidder M.S. Bhattacharyya N. Xing W. Shen S. Milne G.L. et al.Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.Blood. 2012; 119: 3790-3798Crossref PubMed Scopus (182) Google Scholar, 23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 24Weller P.F. Lee C.W. Foster D.W. Corey E.J. Austen K.F. Lewis R.A. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4.Proc Natl Acad Sci U S A. 1983; 80: 7626-7630Crossref PubMed Scopus (378) Google Scholar, 25Murphy R.C. Hammarstrom S. Samuelsson B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells.Proc Natl Acad Sci U S A. 1979; 76: 4275-4279Crossref PubMed Scopus (871) Google Scholar LTC4 is enzymatically converted to the short-lived but powerful smooth muscle constrictor LTD426Carter B.Z. Shi Z.Z. Barrios R. Lieberman M.W. gamma-glutamyl leukotrienase, a gamma-glutamyl transpeptidase gene family member, is expressed primarily in spleen.J Biol Chem. 1998; 273: 28277-28285Crossref PubMed Scopus (47) Google Scholar and then to the stable metabolite LTE4.27Lee C.W. Lewis R.A. Corey E.J. Austen K.F. Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes.Immunology. 1983; 48: 27-35PubMed Google Scholar CysLTs are generated during type 1 hypersensitivity reactions as the product of IgE cross-linking. However, CysLTs are also generated by dendritic cells or macrophages in response to innate signaling pathways initiated by zymosan, peptidoglycan, IgG-opsonized microbes, and house dust mites.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 28Rouzer C.A. Scott W.A. Cohn Z.A. Blackburn P. Manning J.M. Mouse peritoneal macrophages release leukotriene C in response to a phagocytic stimulus.Proc Natl Acad Sci U S A. 1980; 77: 4928-4932Crossref PubMed Scopus (156) Google Scholar, 29Claesson H.E. Lindgren J.A. Gustafsson B. Opsonized bacteria stimulate leukotriene synthesis in human leukocytes.Biochim Biophys Acta. 1985; 836: 361-367Crossref PubMed Scopus (24) Google Scholar, 30McCurdy J.D. Olynych T.J. Maher L.H. Marshall J.S. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells.J Immunol. 2003; 170: 1625-1629Crossref PubMed Scopus (322) Google Scholar All 3 CysLTs are active in vivo, generating vascular leak, bronchoconstriction, mucus hypersecretion, and eosinophil accumulation.31Austen K.F. Maekawa A. Kanaoka Y. Boyce J.A. The leukotriene E4 puzzle: finding the missing pieces and revealing the pathobiologic implications.J Allergy Clin Immunol. 2009; 124: 406-414Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar These functions reflect the capacity of CysLTs to induce signaling through at least 3 G protein–coupled receptors: CysLT1R (a high affinity receptor for LTD4),32Lynch 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 (883) Google Scholar CysLT2R (a lower-affinity receptor for LTC4 and LTD4),33Heise C.E. O'Dowd B.F. Figueroa D.J. Sawyer N. Nguyen T. Im D.S. et al.Characterization of the human cysteinyl leukotriene 2 receptor.J Biol Chem. 2000; 275: 30531-30536Crossref PubMed Scopus (579) Google Scholar and the recently identified CysLT3R with a binding preference for LTE4.34Kanaoka Y. Maekawa A. Austen K.F. Identification of GPR99 as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4.J Biol Chem. 2013; 288: 10967-10972Crossref PubMed Scopus (137) Google Scholar CysLTs are produced at high levels in human patients with allergic diseases, especially in patients with aspirin-exacerbated respiratory disease.35Christie P.E. Tagari P. Ford-Hutchinson A.W. Charlesson S. Chee P. Arm J.P. et al.Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects.Am Rev Respir Dis. 1991; 143: 1025-1029Crossref PubMed Google Scholar Their importance as disease effectors is validated by the clinical efficacy of drugs that block their synthesis36Israel E. Cohn J. Dube 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 or their capacity to induce signaling through CysLT1R.37Israel E. Chervinsky P.S. Friedman B. Van B.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 Recent studies in rodent models have expanded the function of the CysLTs, including a prominent role in priming dendritic cells to induce TH2-type immunity to dust mite allergens.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 38Barrett N.A. Rahman O.M. Fernandez J.M. Parsons M.W. Xing W. Austen K.F. et al.Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.J Exp Med. 2011; 208: 593-604Crossref PubMed Scopus (145) Google Scholar Moreover, the broad expression of CysLT receptors on cells of both the innate39Figueroa D.J. Borish L. Baramki D. Philip G. Austin C.P. Evans J.F. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis.Clin Exp Allergy. 2003; 33: 1380-1388Crossref PubMed Scopus (112) Google Scholar and adaptive40Parmentier C.N. Fuerst E. McDonald J. Bowen H. Lee T.H. Pease J.E. et al.Human T(H)2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1.J Allergy Clin Immunol. 2012; 129: 1136-1142Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar immune systems suggests additional functions and cellular targets to be identified.In this issue of the Journal, Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar report an entirely novel function for the CysLTs, namely the activation and expansion of ILC2s. The fungal allergen species Alternaria can induce the rapid release of IL-33 from epithelial cells and cause the accumulation of eosinophils independently of the adaptive immune system.42Kouzaki H. Iijima K. Kobayashi T. O'Grady S.M. Kita H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses.J Immunol. 2011; 186: 4375-4387Crossref PubMed Scopus (359) Google Scholar Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar found that Alternaria challenge of naive mice caused the production of high CysLT levels, as detected by ELISA from bronchoalveolar lavage fluid obtained 12 hours after a single dose of Alternaria extract. Using flow cytometry and real-time PCR, the investigators demonstrated that Alternaria expanded the population of lung ILC2s (identified as lineage-negative, Thy1.2-positive cells in the lymphocyte gate) and that ILC2s in both naive and Alternaria-challenged mouse lung tissue express CysLT1R protein and transcripts, respectively. This expression did not depend on signal transducer and activator of transcription 6 or the presence of an adaptive immune system. As expected, ILC2s isolated and cultured from the lungs of Alternaria-challenged mice generated abundant quantities of IL-5 and IL-13 when stimulated with IL-33. Surprisingly, LTD4 induced similar quantities of IL-5 and IL-13 from ILC2s, as did IL-33. It also induced the generation of large quantities of IL-4, which was not elicited by IL-33. The intrapulmonary administration of LTC4, LTD4, and LTE4 to naive mice each increased the percentages of ILC2s in the lung that expressed IL-5, as determined by using intracellular cytofluorographic staining. Importantly, pretreatment of the mice with the CysLT1R antagonist montelukast blocked IL-5 generation by ILC2s in response to LTC4 and LTD4, whereas the effects of LTE4 were completely resistant to montelukast treatment. Finally, the intrapulmonary administration of LTD4 did not elicit proliferation of ILC2s when given to naive mice but did potentiate proliferation in the setting of Alternaria challenge.The findings of Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar carry many implications. First, the fact that LTD4 was as potent as IL-33 for inducing ILC2s to generate IL-5 and IL-13 suggests that endogenous CysLTs can amplify the production of effector cytokines through ILC2s, promoting eosinophilia and airway reactivity. Second, the capacity of LTD4, but not IL-33, to elicit the generation of large quantities of IL-4 by ILC2s suggests a potential link to the TH2-priming functions of the CysLTs in mouse models of allergen-induced pulmonary inflammation.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 38Barrett N.A. Rahman O.M. Fernandez J.M. Parsons M.W. Xing W. Austen K.F. et al.Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.J Exp Med. 2011; 208: 593-604Crossref PubMed Scopus (145) Google Scholar Third, CysLTs generated by tissue-resident innate immune cells (dendritic cells, mast cells, and macrophages) in response to natural allergens might contribute not only to breaking tolerance and activating the adaptive immune response but also to driving pathology that is independent of adaptive immunity. Lastly, the fact that LTE4, the most stable and abundant of the CysLTs, can drive IL-5 production through a mechanism that is resistant to CysLT1R antagonists is potentially highly significant. LTE4 induces pulmonary eosinophilia through a pathway that depends on the P2Y12 purinergic receptor43Paruchuri S. Tashimo H. Feng C. Maekawa A. Xing W. Jiang Y. et al.Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.J Exp Med. 2009; 206: 2543-2555Crossref PubMed Scopus (204) Google Scholar and induces cutaneous vascular leak in vivo through a novel CysLT3R.34Kanaoka Y. Maekawa A. Austen K.F. Identification of GPR99 as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4.J Biol Chem. 2013; 288: 10967-10972Crossref PubMed Scopus (137) Google Scholar Both P2Y12 and CysLT3R resist blockade by CysLT1R antagonists, and it is tempting to speculate that one or both receptors might also be expressed by ILC2s and might account for the montelukast-resistant effects of LTE4 identified in the study by Doherty et al.41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar It also seems possible that high levels of LTE4 found in biologic fluids from patients with aspirin-exacerbated respiratory disease could drive effector responses from ILC2s. This would be consistent with the persistent tissue eosinophilia, airway remodeling, and nasal polyposis, frequently with no sensitization to allergens, that characterize this disease. The pathology of allergic inflammation in patients with asthma and allergic gastrointestinal disease is dominated by eosinophil infiltration and the local generation of a characteristic cassette of cytokines (IL-4, IL-5, and IL-13).1Foster P.S. Martinez-Moczygemba M. Huston D.P. Corry D.B. Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease.Pharmacol Ther. 2002; 94: 253-264Crossref PubMed Scopus (69) Google Scholar Although these cytokines can be generated by TH2 cells, studies in both human subjects2Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (884) Google Scholar and rodents3Voehringer D. Reese T.A. Huang X. Shinkai K. Locksley R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.J Exp Med. 2006; 203: 1435-1446Crossref PubMed Scopus (260) Google Scholar, 4Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar, 5Hurst S.D. Muchamuel T. Gorman D.M. Gilbert J.M. Clifford T. Kwan S. et al.New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25.J Immunol. 2002; 169: 443-453Crossref PubMed Scopus (526) Google Scholar have implicated innate cell sources of the same cytokines. In 2010, several laboratories simultaneously reported novel innate lymphoid cells in the mesenteric fat and gut-associated lymphoid tissues that expanded and generated IL-5 and IL-13 in vivo in response to exogenous IL-25 and IL-33 or to helminth infection.6Neill D.R. Wong S.H. Bellosi A. Flynn R.J. Daly M. Langford T.K. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (1592) Google Scholar, 7Saenz S.A. Siracusa M.C. Perrigoue J.G. Spencer S.P. Urban Jr., J.F. Tocker J.E. et al.IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.Nature. 2010; 464: 1362-1366Crossref PubMed Scopus (470) Google Scholar, 8Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. et al.Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.Nature. 2010; 463: 540-544Crossref PubMed Scopus (1477) Google Scholar A similar population was later found in mouse liver, spleen, and lung tissue.9Price A.E. Liang H.E. Sullivan B.M. Reinhardt R.L. Eisley C.J. Erle D.J. et al.Systemically dispersed innate IL-13-expressing cells in type 2 immunity.Proc Natl Acad Sci U S A. 2010; 107: 11489-11494Crossref PubMed Scopus (878) Google Scholar, 10Halim T.Y. Krauss R.H. Sun A.C. Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation.Immunity. 2012; 36: 451-463Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar As such, these studies suggested that cells of the innate immune system could potentially initiate or amplify eosinophilic inflammation at mucosal sites in response to stimuli, such as tissue injury, viral infection, or pathogen-associated molecular patterns, without the requirement for antigen specificity. Shortly thereafter, a cell population with similar characteristics was identified in human intestine, lung, and nasal polyp tissue that expresses CRTH2, the chemoattractant receptor for prostaglandin D2.2Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (884) Google Scholar A recent consensus has reclassified these cells in both mice and human subjects as group 2 innate lymphoid cells (ILC2s).11Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1709) Google Scholar ILC2s arise from a common lymphoid progenitor that expresses the transcriptional repressor inhibitor of DNA binding 2. They are related to group 1 innate lymphoid cells (ILC1s; which include natural killer cells and IFN-γ–generating ILC1s) and group 3 innate lymphoid cells (which generate IL-17 and IL-22). Although ILC2s share the developmental requirement for IL-7 and IL-2 with ILC1s and group 3 innate lymphoid cells, they differ from these other innate lymphoid cells in their expression of retinoic acid receptor–related orphan receptor α and GATA3, a transcription factor also linked to the development of conventional TH2 cells.12Mjosberg J. Bernink J. Golebski K. Karrich J.J. Peters C.P. Blom B. et al.The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells.Immunity. 2012; 37: 649-659Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 13Halim T.Y. MacLaren A. Romanish M.T. Gold M.J. McNagny K.M. Takei F. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation.Immunity. 2012; 37: 463-474Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar The role of ILC2s in human disease is speculative at this stage; however, mouse models suggest that this cell population might provide effector cytokines at levels sufficient to eliminate helminths,8Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. et al.Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.Nature. 2010; 463: 540-544Crossref PubMed Scopus (1477) Google Scholar amplify antigen-induced airway hyperreactivity,14Barlow J.L. Bellosi A. Hardman C.S. Drynan L.F. Wong S.H. Cruickshank J.P. et al.Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity.J Allergy Clin Immunol. 2012; 129: 191-198Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar trigger eosinophilic pulmonary inflammation, and promote both airway hyperreactivity and tissue healing after influenza virus infection.15Chang Y.J. Kim H.Y. Albacker L.A. Baumgarth N. McKenzie A.N. Smith D.E. et al.Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity.Nat Immunol. 2011; 12: 631-638Crossref PubMed Scopus (629) Google Scholar, 16Monticelli L.A. Sonnenberg G.F. Abt M.C. Alenghat T. Ziegler C.G. Doering T.A. et al.Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.Nat Immunol. 2011; 12: 1045-1054Crossref PubMed Scopus (1082) Google Scholar In each instance their activation is thought to occur principally through IL-33, IL-25, and/or thymic stromal lymphopoietin generated by the perturbed barrier cells. Cysteinyl leukotrienes (CysLTs) are arachidonic acid–derived lipid mediators and the most potent known constrictors of smooth muscle.17Weiss J.W. Drazen J.M. McFadden Jr., E.R. Weller P.F. Corey E.J. Lewis R.A. et al.Comparative bronchoconstrictor effects of histamine, leukotriene C, and leukotriene D in normal human volunteers.Trans Assoc Am Physicians. 1982; 95: 30-35PubMed Google Scholar Leukotriene (LT) C4, the parent CysLT, is generated through the 5-lipoxygenase and LTC4 synthase pathway18Reid G.K. Kargman S. Vickers P.J. Mancini J.A. Leveille C. 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Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4.Proc Natl Acad Sci U S A. 1983; 80: 7626-7630Crossref PubMed Scopus (378) Google Scholar, 25Murphy R.C. Hammarstrom S. Samuelsson B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells.Proc Natl Acad Sci U S A. 1979; 76: 4275-4279Crossref PubMed Scopus (871) Google Scholar LTC4 is enzymatically converted to the short-lived but powerful smooth muscle constrictor LTD426Carter B.Z. Shi Z.Z. Barrios R. Lieberman M.W. gamma-glutamyl leukotrienase, a gamma-glutamyl transpeptidase gene family member, is expressed primarily in spleen.J Biol Chem. 1998; 273: 28277-28285Crossref PubMed Scopus (47) Google Scholar and then to the stable metabolite LTE4.27Lee C.W. Lewis R.A. Corey E.J. Austen K.F. Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes.Immunology. 1983; 48: 27-35PubMed Google Scholar CysLTs are generated during type 1 hypersensitivity reactions as the product of IgE cross-linking. However, CysLTs are also generated by dendritic cells or macrophages in response to innate signaling pathways initiated by zymosan, peptidoglycan, IgG-opsonized microbes, and house dust mites.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 28Rouzer C.A. Scott W.A. Cohn Z.A. Blackburn P. Manning J.M. Mouse peritoneal macrophages release leukotriene C in response to a phagocytic stimulus.Proc Natl Acad Sci U S A. 1980; 77: 4928-4932Crossref PubMed Scopus (156) Google Scholar, 29Claesson H.E. Lindgren J.A. Gustafsson B. Opsonized bacteria stimulate leukotriene synthesis in human leukocytes.Biochim Biophys Acta. 1985; 836: 361-367Crossref PubMed Scopus (24) Google Scholar, 30McCurdy J.D. Olynych T.J. Maher L.H. Marshall J.S. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells.J Immunol. 2003; 170: 1625-1629Crossref PubMed Scopus (322) Google Scholar All 3 CysLTs are active in vivo, generating vascular leak, bronchoconstriction, mucus hypersecretion, and eosinophil accumulation.31Austen K.F. Maekawa A. Kanaoka Y. Boyce J.A. The leukotriene E4 puzzle: finding the missing pieces and revealing the pathobiologic implications.J Allergy Clin Immunol. 2009; 124: 406-414Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar These functions reflect the capacity of CysLTs to induce signaling through at least 3 G protein–coupled receptors: CysLT1R (a high affinity receptor for LTD4),32Lynch 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 (883) Google Scholar CysLT2R (a lower-affinity receptor for LTC4 and LTD4),33Heise C.E. O'Dowd B.F. Figueroa D.J. Sawyer N. Nguyen T. Im D.S. et al.Characterization of the human cysteinyl leukotriene 2 receptor.J Biol Chem. 2000; 275: 30531-30536Crossref PubMed Scopus (579) Google Scholar and the recently identified CysLT3R with a binding preference for LTE4.34Kanaoka Y. Maekawa A. Austen K.F. Identification of GPR99 as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4.J Biol Chem. 2013; 288: 10967-10972Crossref PubMed Scopus (137) Google Scholar CysLTs are produced at high levels in human patients with allergic diseases, especially in patients with aspirin-exacerbated respiratory disease.35Christie P.E. Tagari P. Ford-Hutchinson A.W. Charlesson S. Chee P. Arm J.P. et al.Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects.Am Rev Respir Dis. 1991; 143: 1025-1029Crossref PubMed Google Scholar Their importance as disease effectors is validated by the clinical efficacy of drugs that block their synthesis36Israel E. Cohn J. Dube 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 or their capacity to induce signaling through CysLT1R.37Israel E. Chervinsky P.S. Friedman B. Van B.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 Recent studies in rodent models have expanded the function of the CysLTs, including a prominent role in priming dendritic cells to induce TH2-type immunity to dust mite allergens.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 38Barrett N.A. Rahman O.M. Fernandez J.M. Parsons M.W. Xing W. Austen K.F. et al.Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.J Exp Med. 2011; 208: 593-604Crossref PubMed Scopus (145) Google Scholar Moreover, the broad expression of CysLT receptors on cells of both the innate39Figueroa D.J. Borish L. Baramki D. Philip G. Austin C.P. Evans J.F. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis.Clin Exp Allergy. 2003; 33: 1380-1388Crossref PubMed Scopus (112) Google Scholar and adaptive40Parmentier C.N. Fuerst E. McDonald J. Bowen H. Lee T.H. Pease J.E. et al.Human T(H)2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1.J Allergy Clin Immunol. 2012; 129: 1136-1142Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar immune systems suggests additional functions and cellular targets to be identified. In this issue of the Journal, Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar report an entirely novel function for the CysLTs, namely the activation and expansion of ILC2s. The fungal allergen species Alternaria can induce the rapid release of IL-33 from epithelial cells and cause the accumulation of eosinophils independently of the adaptive immune system.42Kouzaki H. Iijima K. Kobayashi T. O'Grady S.M. Kita H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses.J Immunol. 2011; 186: 4375-4387Crossref PubMed Scopus (359) Google Scholar Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar found that Alternaria challenge of naive mice caused the production of high CysLT levels, as detected by ELISA from bronchoalveolar lavage fluid obtained 12 hours after a single dose of Alternaria extract. Using flow cytometry and real-time PCR, the investigators demonstrated that Alternaria expanded the population of lung ILC2s (identified as lineage-negative, Thy1.2-positive cells in the lymphocyte gate) and that ILC2s in both naive and Alternaria-challenged mouse lung tissue express CysLT1R protein and transcripts, respectively. This expression did not depend on signal transducer and activator of transcription 6 or the presence of an adaptive immune system. As expected, ILC2s isolated and cultured from the lungs of Alternaria-challenged mice generated abundant quantities of IL-5 and IL-13 when stimulated with IL-33. Surprisingly, LTD4 induced similar quantities of IL-5 and IL-13 from ILC2s, as did IL-33. It also induced the generation of large quantities of IL-4, which was not elicited by IL-33. The intrapulmonary administration of LTC4, LTD4, and LTE4 to naive mice each increased the percentages of ILC2s in the lung that expressed IL-5, as determined by using intracellular cytofluorographic staining. Importantly, pretreatment of the mice with the CysLT1R antagonist montelukast blocked IL-5 generation by ILC2s in response to LTC4 and LTD4, whereas the effects of LTE4 were completely resistant to montelukast treatment. Finally, the intrapulmonary administration of LTD4 did not elicit proliferation of ILC2s when given to naive mice but did potentiate proliferation in the setting of Alternaria challenge. The findings of Doherty et al41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar carry many implications. First, the fact that LTD4 was as potent as IL-33 for inducing ILC2s to generate IL-5 and IL-13 suggests that endogenous CysLTs can amplify the production of effector cytokines through ILC2s, promoting eosinophilia and airway reactivity. Second, the capacity of LTD4, but not IL-33, to elicit the generation of large quantities of IL-4 by ILC2s suggests a potential link to the TH2-priming functions of the CysLTs in mouse models of allergen-induced pulmonary inflammation.23Barrett N.A. Maekawa A. Rahman O.M. Austen K.F. Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.J Immunol. 2009; 182: 1119-1128Crossref PubMed Scopus (188) Google Scholar, 38Barrett N.A. Rahman O.M. Fernandez J.M. Parsons M.W. Xing W. Austen K.F. et al.Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.J Exp Med. 2011; 208: 593-604Crossref PubMed Scopus (145) Google Scholar Third, CysLTs generated by tissue-resident innate immune cells (dendritic cells, mast cells, and macrophages) in response to natural allergens might contribute not only to breaking tolerance and activating the adaptive immune response but also to driving pathology that is independent of adaptive immunity. Lastly, the fact that LTE4, the most stable and abundant of the CysLTs, can drive IL-5 production through a mechanism that is resistant to CysLT1R antagonists is potentially highly significant. LTE4 induces pulmonary eosinophilia through a pathway that depends on the P2Y12 purinergic receptor43Paruchuri S. Tashimo H. Feng C. Maekawa A. Xing W. Jiang Y. et al.Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.J Exp Med. 2009; 206: 2543-2555Crossref PubMed Scopus (204) Google Scholar and induces cutaneous vascular leak in vivo through a novel CysLT3R.34Kanaoka Y. Maekawa A. Austen K.F. Identification of GPR99 as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4.J Biol Chem. 2013; 288: 10967-10972Crossref PubMed Scopus (137) Google Scholar Both P2Y12 and CysLT3R resist blockade by CysLT1R antagonists, and it is tempting to speculate that one or both receptors might also be expressed by ILC2s and might account for the montelukast-resistant effects of LTE4 identified in the study by Doherty et al.41Doherty T. Khorram N. Lund S. Mehta A.K. Croft M. Broide D. Lung type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production.J Allergy Clin Immunol. 2013; 132: 205-213Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar It also seems possible that high levels of LTE4 found in biologic fluids from patients with aspirin-exacerbated respiratory disease could drive effector responses from ILC2s. This would be consistent with the persistent tissue eosinophilia, airway remodeling, and nasal polyposis, frequently with no sensitization to allergens, that characterize this disease. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine productionJournal of Allergy and Clinical ImmunologyVol. 132Issue 1PreviewCysteinyl leukotrienes (CysLTs) contribute to asthma pathogenesis, in part through cysteinyl leukotriene receptor 1 (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2s) potently produce IL-5 and IL-13. Full-Text PDF" @default.
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