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Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines

2018; Elsevier BV; Volume: 141; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2018.02.034

ISSN

1097-6825

Autores

Taylor A. Doherty, David H. Broide,

Tópico(s)

Asthma and respiratory diseases

Resumo

The role of group 2 innate lymphoid cells (ILC2s) in patients with allergic diseases has recently gained considerable focus because ILC2s are a potent source of the TH2 cytokines IL-4, IL-5, IL-9, and IL-13 independent of conventional T cells.1Cavagnero K. Doherty T.A. Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease.J Cytokine Biol. 2017; 2Crossref PubMed Google Scholar ILC2s are a rare population of cells that lack lineage-specific markers (T-cell, B-cell, or other leukocyte lineage markers) and thus were largely hidden from investigation until the last decade. The discovery of ILC2s was based on studies to identify cells in mice that were responsive to the epithelial cytokines IL-25 and IL-33.2Doherty T.A. At the bench: understanding group 2 innate lymphoid cells in disease.J Leukoc Biol. 2015; 97: 455-467Crossref PubMed Scopus (48) Google Scholar Therefore the early dogma of ILC2 regulation has relied on a model whereby IL-25, IL-33, and thymic stromal lymphopoietin derived from damaged epithelial cells dominantly drives ILC2 activation to initiate type 2 inflammation. Although there is an abundance of support for this model, other paradigms of ILC2 regulation, including modulation by multiple lipid mediators, have emerged that might be equally critical in specific disease contexts.1Cavagnero K. Doherty T.A. Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease.J Cytokine Biol. 2017; 2Crossref PubMed Google Scholar Importantly, both ILC2s and lipid mediators are increased in tissues from patients with asthma, chronic rhinosinusitis, and atopic dermatitis and contribute to pathogenesis in animal models.1Cavagnero K. Doherty T.A. Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease.J Cytokine Biol. 2017; 2Crossref PubMed Google Scholar, 3Schauberger E. Peinhaupt M. Cazares T. Lindsley A.W. Lipid mediators of allergic disease: pathways, treatments, and emerging therapeutic targets.Curr Allergy Asthma Rep. 2016; 16: 48Crossref PubMed Scopus (52) Google Scholar The first report to show that ILC2 responses are regulated by lipids demonstrated that prostaglandin (PG) D2 increased IL-13 production from human peripheral blood ILC2s in the presence of IL-33 and IL-25 and also showed that lipoxin A4 could inhibit ILC2 activation.4Barnig C. Cernadas M. Dutile S. Liu X. Perrella M.A. Kazani S. et al.Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma.Sci Transl Med. 2013; 5: 174ra26Crossref PubMed Scopus (351) Google Scholar Shortly afterward, mouse lung ILC2s were reported to be rapidly and robustly activated by the cysteinyl leukotriene (CysLT) leukotriene (LT) D4 in vitro and in vivo.5Doherty 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 (305) Google Scholar The list of lipids that modulate ILC2 function continues to expand and includes the positive regulators PGD2, CysLTs (LTC4, LTD4, and LTE4), and LTB4; the inhibitors lipoxin A4 and PGI2; and the omega-3 derivative maresin-1 (Fig 1).6von 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, 7Zhou W. Toki S. Zhang J. Goleniewksa K. Newcomb D.C. Cephus J.Y. et al.Prostaglandin I2 signaling and inhibition of group 2 innate lymphoid cell responses.Am J Respir Crit Care Med. 2016; 193: 31-42Crossref PubMed Scopus (97) Google Scholar, 8Krishnamoorthy N. Burkett P.R. Dalli J. Abdulnour R.E. Colas R. Ramon S. et al.Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation.J Immunol. 2015; 194: 863-867Crossref PubMed Scopus (133) Google Scholar Importantly, recent work has demonstrated that sex hormones regulate ILC2s because androgens are suppressive in ILC2 function and numbers of circulating ILC2s are increased in women with severe asthma compared with men.9Cephus J.Y. Stier M.T. Fuseini H. Yung J.A. Toki S. Bloodworth M.H. et al.Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation.Cell Rep. 2017; 21: 2487-2499Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 10Laffont S. Blanquart E. Guery J.C. Sex differences in asthma: a key role of androgen-signaling in group 2 innate lymphoid cells.Front Immunol. 2017; 8: 1069Crossref PubMed Scopus (40) Google Scholar Furthermore, androgens reduce leukotriene biosynthesis that is increased in female compared with male mice.11Pace S. Pergola C. Dehm F. Rossi A. Gerstmeier J. Troisi F. et al.Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.J Clin Invest. 2017; 127: 3167-3176Crossref PubMed Scopus (58) Google Scholar Overall, lipid mediators are likely critical modulators of innate lymphoid cell (ILC) function in patients with allergic diseases. In this issue of the Journal, Maric et al12Maric J. Ravindran A. Mazzurana L. Björklund Å.K. Van Acker A. Rao A. et al.Prostaglandin E2 suppresses human group 2 innate lymphoid cell function.J Allergy Clin Immunol. 2018; 141: 1761-1773Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar show that PGE2 also inhibits human ILC2 function. The authors purified human ILC2s from peripheral blood and tonsils and stimulated cells with IL-2, IL-25, IL-33, and thymic stromal lymphopoietin. The addition of PGE2 resulted in reduced GATA3 expression, as well as decreased IL-5 and IL-13 production. Furthermore, PGE2 induced downregulation of IL-2 receptor α (CD25) and led to reduced ILC2 proliferation. PGE2 has 4 different receptors, EP1 to EP4, encoded by the PTGER1 to PTGER4 genes, respectively. Single-cell RNA sequencing and quantitative RT-PCR of human ILC2s revealed expression of PTGER2 and PTGER4 but not PTGER1 and PTGER3. The authors then performed similar PGE2 ILC2 culture studies with selective EP2 and EP4 antagonists and found that dual inhibition of EP2 and EP4 was required to reverse the effects of PGE2. This suggests that both EP2 and EP4 receptors are used by PGE2 to inhibit ILC2 responses. A major strength of this work is that it is highly translational by using human ILC2s, although a limitation is the lack of in vivo data. Additionally, findings in ILC2s isolated from peripheral blood might not fully represent mucosal ILC2 activities. Future work is required to assess whether PGE2 reduces mucosal ILC2 responses during type 2 lung inflammation in vivo. In the context of human allergic diseases, ILC2s are exposed to a multitude of mediators that activate or inhibit their function, which likely results in fine-tuning of ILC2 responses. From several animal model studies, it is clear that epithelial cytokines, namely IL-33, are responsible for initiating ILC2 activation to allergens and viruses.1Cavagnero K. Doherty T.A. Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease.J Cytokine Biol. 2017; 2Crossref PubMed Google Scholar However, because activated eosinophils and mast cells, which are the dominant sources of PGD2 and CysLTs,3Schauberger E. Peinhaupt M. Cazares T. Lindsley A.W. Lipid mediators of allergic disease: pathways, treatments, and emerging therapeutic targets.Curr Allergy Asthma Rep. 2016; 16: 48Crossref PubMed Scopus (52) Google Scholar accumulate in tissues during chronic allergic diseases, the possibility exists that lipids might more dominantly regulate ILC2s compared with epithelial cytokines during later stages of type 2 inflammation. Furthermore, macrophages and epithelial cells that produce proresolving lipid mediators, as well as PGE2, could play a critical role in dampening inappropriately activated ILC2 responses (Fig 1). Modulation of ILC2 function by lipid mediators likely involves several signaling pathways that might mirror those found in T cells, including the calcium/calcineurin/nuclear factor of activated T cells (NFAT) pathway (Fig 1).13Lone A.M. Tasken K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells.Front Immunol. 2013; 4: 130Crossref PubMed Scopus (92) Google Scholar Recently, CysLTs were demonstrated to rapidly induce calcium influx and nuclear NFAT translocation that synergistically enhanced IL-33–induced ILC2 activation.6von 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, 14Lund 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 Furthermore, both NFAT and phosphoinositide 3-kinase pathway activation mediates PGD2-induced cytokine production in TH2 cells through the receptor chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes, which is also expressed on ILC2s.13Lone A.M. Tasken K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells.Front Immunol. 2013; 4: 130Crossref PubMed Scopus (92) Google Scholar PGE2 binding of T-cell EP2 and EP4 leads to increased cyclic AMP (cAMP) levels that negatively regulate IL-2 production, as well IL-2 receptor (CD25) expression; the latter effect is similar to the current findings in ILC2s.12Maric J. Ravindran A. Mazzurana L. Björklund Å.K. Van Acker A. Rao A. et al.Prostaglandin E2 suppresses human group 2 innate lymphoid cell function.J Allergy Clin Immunol. 2018; 141: 1761-1773Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 13Lone A.M. Tasken K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells.Front Immunol. 2013; 4: 130Crossref PubMed Scopus (92) Google Scholar PGI2, which is also inhibitory to T-cell cytokine production, similarly induces increases in cAMP and leads to activation of protein kinase A and downregulation of nuclear factor κB (NF-κB) signaling.13Lone A.M. Tasken K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells.Front Immunol. 2013; 4: 130Crossref PubMed Scopus (92) Google Scholar Thus cAMP levels and NFAT activation are likely critical players in how eicosanoids mediate ILC2 responses, but further studies will need to confirm whether such findings in T cells translate to ILC2s. Although lipid mediators contribute to several chronic allergic diseases, aspirin-exacerbated respiratory disease (AERD) appears to involve dysregulation of lipid mediators, namely PGD2 and CysLTs, at the core of pathogenesis.15Woessner K.M. Update on aspirin-exacerbated respiratory disease.Curr Allergy Asthma Rep. 2017; 17: 2Crossref PubMed Scopus (21) Google Scholar A very recent report demonstrated that ILC2s are recruited to the nasal mucosa during COX-1 inhibitor reactions in patients with AERD, and multiple studies have shown that eosinophilic nasal polyps are enriched with ILC2s.1Cavagnero K. Doherty T.A. Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease.J Cytokine Biol. 2017; 2Crossref PubMed Google Scholar, 16Eastman J.J. Cavagnero K.J. Deconde A.S. Kim A.S. Karta M.R. Broide D.H. et al.Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2017; 140: 101-108.e3Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Interestingly, some patients with AERD have shown PGE2 hyporesponsiveness in granulocytes and polyp fibroblasts,17Laidlaw T.M. Cutler A.J. Kidder M.S. Liu T. Cardet J.C. Chhay H. et al.Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2014; 133: 1692-1701.e3Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 18Cahill K.N. Raby B.A. Zhou X. Guo F. Thibault D. Baccarelli A. et al.Impaired E prostanoid2 expression and resistance to prostaglandin E2 in nasal polyp fibroblasts from subjects with aspirin-exacerbated respiratory disease.Am J Respir Cell Mol Biol. 2016; 54: 34-40Crossref PubMed Scopus (47) Google Scholar and if ILC2s in patients with AERD are also resistant to PGE2, then perhaps this is one mechanism by which persistent ILC2 activation could contribute to disease. As with the entire ILC2 field, we are witnessing a rapidly emerging and exciting window into novel mechanisms of allergic diseases. Prostaglandin E2 suppresses human group 2 innate lymphoid cell functionJournal of Allergy and Clinical ImmunologyVol. 141Issue 5PreviewGroup 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation. 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