Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 1; pp. 205 - 213
• Main Authors: Doherty, Taylor A., Khorram, Naseem, Lund, Sean, Mehta, Amit Kumar, Croft, Michael, Broide, David H.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2013; Elsevier; Elsevier Limited
• Subjects: Alternaria; Alternaria - immunology; Animals; antagonists; Asthma; Biological and medical sciences; calcium; Chlorophyll; CysLT1R; cysteinyl leukotrienes; Cytokines; Cytokines - biosynthesis; DNA-Binding Proteins - physiology; eosinophilia; Female; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; genes; Human subjects; Immune system; interleukin-13; interleukin-4; interleukin-5; interleukin-7; Leukotriene D4 - pharmacology; leukotrienes; Lung - immunology; Lungs; lymphocytes; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pathogenesis; Receptors, Leukotriene - physiology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; signal transduction; STAT6 Transcription Factor - physiology; T cell receptors; Th2 Cells - immunology; transcription factors; type 2 innate lymphoid cells; IL-7R; TCR; TSLP; FACS; BAL; CysLT; Asthma; ILC2; CysLT1R; FITC; type 2 innate lymphoid cells; APC; LTE4; PE; cysteinyl leukotrienes; LTC4; STAT6; LTD4; RAG2; WT; Lung disease; Immunopathology; Lymphoid cell; Respiratory disease; Leukotriene receptor; Arachidonic acid derivatives; Lung; Cytokine; Biosynthesis; Respiratory system; Leukotriene; Regulation(control); Immunology; Eicosanoid; T-Lymphocyte; Bronchus disease; Th2 lymphocyte; Obstructive pulmonary disease
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.03.048

Cysteinyl 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. We hypothesized that lung ILC2s might be activated by leukotrienes through CysLT1R. ILC2s (Thy1.2+ lineage-negative lymphocytes) and CysLT1R were detected in the lungs of wild-type, signal transducer and activator of transcription 6–deficient (STAT6−/−), and recombination-activating gene 2–deficient (RAG2−/−) mice by means of flow cytometry. TH2 cytokine levels were measured in purified lung ILC2s stimulated with leukotriene D4 (LTD4) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by using Fluo-4 intensity. Intranasal leukotriene C4, D4, and E4 were administered to naive mice, and levels of ILC2 IL-5 production were determined. Finally, LTD4 was coadministered with Alternaria species repetitively to RAG2−/− mice (with ILC2s) and IL-7 receptor–deficient mice (lack ILC2s), and total ILC2 numbers, proliferation (Ki-67+), and bronchoalveolar lavage fluid eosinophil numbers were measured. CysLT1R was expressed on lung ILC2s from wild-type, RAG2−/−, and STAT6−/− naive and Alternaria species–challenged mice. In vitro LTD4 induced ILC2s to rapidly generate high levels of IL-5 and IL-13 within 6 hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2s. LTD4 administered in vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast before treatment. Finally, LTD4 potentiated Alternaria species–induced eosinophilia, as well as ILC2 accumulation and proliferation. We present novel data that CysLT1R is expressed on ILC2s and LTD4 potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD4 potentiates Alternaria species–induced eosinophilia and ILC2 proliferation and accumulation.