title: Prolonged activation of IL-5-producing ILC2 causes pulmonary arterial hypertrophy.
abstract: IL-33 is one of the critical cytokines that activates group 2 innate lymphoid cells (ILC2s) and mediates allergic reactions. Accumulating evidence suggests that IL-33 is also involved in the pathogenesis of several chronic inflammatory diseases. Previously, we generated an IL-5 reporter mouse and revealed that lung IL-5-producing ILC2s played essential roles in regulating eosinophil biology. In this study, we evaluated the consequences of IL-33 administration over a long period, and we observed significant expansion of ILC2s and eosinophils surrounding pulmonary arteries. Unexpectedly, pulmonary arteries showed severe occlusive hypertrophy that was ameliorated in IL-5- or eosinophil-deficient mice, but not in Rag2-deficient mice. This indicates that IL-5-producing ILC2s and eosinophils play pivotal roles in pulmonary arterial hypertrophy. Administration of a clinically used vasodilator was effective in reducing IL-33-induced hypertrophy and repressed the expansion of ILC2s and eosinophils. Taken together, these observations demonstrate a previously unrecognized mechanism in the development of pulmonary arterial hypertrophy and the causative roles of ILC2 in the process.
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.|Department of Immune Regulation, The Research Centre for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikutani
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.|Molecular and Environmental Pathology, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, Niigata, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Fukuoka
authors.affiliation: Department of Immune Regulation, The Research Centre for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
authors.forename: Fujimi
authors.initials: F
authors.lastname: Kudo
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|JST, PRESTO, Saitama, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: JST, PRESTO, Saitama, Japan.|Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.|Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.|Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.|JST, PRESTO, Saitama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Immune Regulation, The Research Centre for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.|Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004804:Eosinophils / Q000276:immunology*; D006984:Hypertrophy; D007113:Immunity, Innate; D000067596:Interleukin-33 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D000067596:Interleukin-33; D015848:Interleukin-5; C499308:Rag2 protein, mouse