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JCI Insight. 2017 Apr 6;2(7):e90721. doi: 10.1172/jci.insight.90721.

Prolonged activation of IL-5-producing ILC2 causes pulmonary arterial hypertrophy.

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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.
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.
Department of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, Niigata, Japan.
Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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.
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.
Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan.


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.

Conflict of interest statement

Conflict of interest: JF is the representative director of Pathology Institute Corp and owns its stocks.

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