Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines Maryam Salimi,

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Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines Maryam Salimi, DPhil, MD, Linda Stöger, MSc, Wei Liu, MSc, Simei Go, BSc, Ian Pavord, F Med Sci, Paul Klenerman, F Med Sci, Graham Ogg, DPhil, FRCP, Luzheng Xue, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 4, Pages 1090-1100.e11 (October 2017) DOI: 10.1016/j.jaci.2016.12.958 Copyright © 2017 The Authors Terms and Conditions

Fig 1 Increased expression of CysLT1 by ILC2s in patients with atopic dermatitis (AD). A, mRNA for cysLT receptors in cultured ILC2s with quantitative RT-PCR. B, Expression of CysLT1 with flow cytometry. C and D, CysLT1+ ILC2s detected in PBMCs from healthy subjects and patients with AD (Fig 1, C) and cohort mean fluorescence intensity CysLT1 (Fig 1, D). FSC, Forward scatter. E, mRNA for CysLT1 in blood ILC2s. *P < .05 (Fig 1, A, n = 10; Fig 1, D, n = 4-8; Fig 1, E, n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Migration of cultured ILC2s in response to cysLTs. A, Migration of ILC2s to cysLTs or IL-33 examined with chemotaxis assays. B, Migration of ILC2s in response to LTE4, PGD2, IL-33, IL-25, and TSLP alone or in combination in the presence/absence of montelukast. *P < .05. Data in Fig 2, A, are representative of 4 experiments (Fig 2, B, n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Effect of cysLTs on apoptosis of cultured ILC2s. A, Annexin-V+ cells detected by using flow cytometry after IL-2 withdrawal in the presence/absence of cysLTs. B and C, Annexin-V+ cells at 18 hours after IL-2 withdrawal in the presence of LTC4 (dashed line), LTD4 (dotted line), or LTE4 (solid line; Fig 3, B) or LTE4/montelukast (Fig 3, C). *P < .05. Data in Fig 3, A, are representative of 3 experiments (Fig 3, B, n = 4; Fig 3, C, n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Effect of cysLTs and CysLT1 antagonist on IL-13 production in cultured ILC2s. A, IL-13 concentrations in cell supernatants measured with ELISA after treatment with LTC4 (dashed line), LTD4 (dotted line), or LTE4 (solid line). B, IL-13 production by ILC2s induced by 100 nmol/L LTE4 in the presence of montelukast. Data in Fig 4, A, are representative of 5 experiments (Fig 4, B, n = 1). EC50, Half maximal effective concentration; IC50, half maximal inhibitory concentration. Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 5 LTE4 enhancement of effects of PGD2 and epithelial cytokines on cytokine production by cultured ILC2s. Cytokine concentrations after ILC2 treatment with LTE4 and PGD2 alone or in combination (A) or LTE4, IL-33, IL-25, and TSLP alone or in combination (B) in the presence (black bar)/absence (white bars) of montelukast. Cytokines were measured with the multiplex bead array. *P < .05 (n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 6 Effect of IL-2 and other stimulators on cytokine and receptor expression in cultured ILC2s. Cytokine concentrations in supernatants (A) or mRNA levels of receptors in ILC2s (B) after treatment with combinations of LTE4, PGD2, IL-33, IL-25, and TSLP with or without montelukast in the presence (black bars)/absence (white bars) of IL-2 measured with the multiplex bead array (Fig 6, A) or quantitative RT-PCR (Fig 6, B). *P < .05 (n = 3-5). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig 7 Effect of endogenous cysLTs on cytokine production in cultured ILC2s. A, Levels of LTE4 in supernatants of mast cells treated with medium (white bar, ns) or IgE/anti-IgE with (gray bar, IgE+MK) or without (black bar, IgE) MK886. B and C, Protein (Fig 7, B) and mRNA (Fig 7, C) levels of cytokines of ILC2s after incubation with supernatants with or without montelukast for 4 hours. *P < .05 (n = 4). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E1 ILC2 isolation. ILC2s isolated from human blood were lineage marker negative (CD3, CD14, CD19, CD56, CD11c, CD11b, FcεRI, TCRγδ, TCRα,β and CD123), CD45high, IL-7 receptor α–positive, and CRTH2+ cells. FSC, Forward scatter. Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E2 GPR99 is not expressed by human ILC2s and TH2 cells. The protein level of GPR99 in cell lysates was detected by using Western blotting. NIH3T3 cells were used as a positive control. Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E3 CysLTs do not affect proliferation of ILC2s in culture. Levels of Cell Trace Violet in ILC2s were measured with flow cytometry at day 4 after cell labeling with Cell Trace Violet and then incubation with 100 nmol/L LTC4, LTD4, or LTE4 (n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E4 LTE4 synergistically enhanced gene transcription of type 2 cytokines induced by PGD2 in cultured human ILC2s. mRNA levels of type 2 cytokines in ILC2s after treatment with LTE4 and PGD2 alone or their combination for 4 hours were determined by using quantitative RT-PCR. *P < .05 (n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E5 LTE4 and PGD2 enhanced the effects of epithelial cytokines on type 2 cytokine production by ILC2s ex vivo. A, IL-5+ ILC2s detected in fresh PBMCs after stimulation with IL-33 (50 ng/mL), IL-25 (50 ng/mL), and TSLP (50 ng/mL) or a combination of these epithelial cytokines with LTE4 (50 nmol/L) and PGD2 (100 nmol/L) by using intracellular staining. B, Proportion of type 2 cytokine (IL-5 and IL-13)–positive cells in gated Lin−CD45+ cells after indicated treatments. *P < .05. Data in Fig E5, A, are representative of 3 independent experiments (Fig E5, B, n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E6 IL-2–enhanced cytokine production in ILC2s in response to LTE4, IL-33, IL-25, and their combinations. IL-13 concentrations in ILC2 culture after incubation with LTE4, IL-33, or IL-25 or their combinations in the presence (black bars) or absence (white bars) of IL-2 were measured with the multiplex bead array. *P < .05 (n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E7 Effect of combination of IL-2 and other stimulators on gene expression of cytokines in ILC2 cells. mRNA levels of cytokines in cultured ILC2s after treatment with different combinations of LTE4, PGD2, IL-33, IL-25, and TSLP with or without montelukast in the presence (black bars) or absence (white bars) of IL-2 for 4 hours were measured with quantitative RT-PCR. *P < .05 (n = 3). Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions

Fig E8 Relationship between IL1RL1 gene regulation and cytokine productions in ILC2s after various treatments was analyzed by using Spearman analysis. Journal of Allergy and Clinical Immunology 2017 140, 1090-1100.e11DOI: (10.1016/j.jaci.2016.12.958) Copyright © 2017 The Authors Terms and Conditions