• Taylor A Doherty, Naseem Khorram, Sean Lund, Amit Kumar Mehta, Michael Croft, and David H Broide.
• Department of Medicine, University of California, La Jolla, CA 92093-0635, USA. tdoherty@ucsd.edu
• J. Allergy Clin. Immunol. 2013 Jul 1;132(1):205-13.

BackgroundCysteinyl 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.ObjectivesWe hypothesized that lung ILC2s might be activated by leukotrienes through CysLT1R.MethodsILC2s (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. T(H)2 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.ResultsCysLT1R 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.ConclusionsWe 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.Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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