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A recent study showed that peripheral IL\u201033 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL\u201033\/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that <jats:italic>St2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> substantially reduced scratching behaviors in 2,4\u2010dinitrofluorobenzene (DNFB)\u2010induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water\u2010induced dry skin in mice. Intrathecal administration of the neutralizing anti\u2010ST2 or anti\u2010IL\u201033 antibody remarkably decreased the scratching response in DNFB\u2010induced ACD mice. Expression of spinal IL\u201033 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL\u201033 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by <jats:italic>St2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL\u201033 pretreatment exacerbated gastrin\u2010releasing peptide (GRP)\u2010evoked scratching behaviors. This increased gastrin\u2010releasing peptide receptor (GRPR) expression was abolished by <jats:italic>St2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>. <jats:italic>Tnf\u2010\u03b1<\/jats:italic> upregulation was suppressed by <jats:italic>St2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>. Our results indicate that the spinal IL\u201033\/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2\u2010STAT3 cascade activation, promoting TNF\u2010\u03b1 release to regulate the GRP\/GRPR signaling\u2010related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.<\/jats:p>","DOI":"10.1002\/glia.23639","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T10:25:47Z","timestamp":1557829547000},"page":"1680-1693","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Spinal IL\u201033\/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2\u2010STAT3 cascade"],"prefix":"10.1002","volume":"67","author":[{"given":"Lixia","family":"Du","sequence":"first","affiliation":[{"name":"Department of Integrative Medicine and Neurobiology Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University  Shanghai People's Republic of 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