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To establish whether as well as the mechanisms by which the activation of Janus kinases (JAKs) is involved in the development of steroid resistance in asthma, murine steroid\u2010resistant models of the proliferation of group 2 innate lymphoid cells (ILC2s) in vitro and asthmatic airway inflammation in vivo were analysed. ILC2s in the lungs of BALB\/c mice were sorted and then incubated with IL\u201033, thymic stromal lymphopoietin (TSLP), and\/or IL\u20107 with or without dexamethasone (10\u2009nM), the pan\u2010JAK inhibitor, delgocitinib (1\u201310\u2009000\u2009nM), and\/or the Bcl\u2010xL inhibitor, navitoclax (1\u2013100\u2009nM), followed by the detection of viable and apoptotic cells. The anti\u2010apoptotic factor, Bcl\u2010xL was detected in ILC2s by flow cytometry. As a steroid\u2010resistant asthma model, ovalbumin (OVA)\u2010sensitized BALB\/c mice were intratracheally challenged with OVA at a high dose of 500\u2009\u03bcg four times. Dexamethasone (1\u2009mg\/kg, i.p.), delgocitinib (3\u201330\u2009mg\/kg, p.o.), or navitoclax (30\u2009mg\/kg, p.o.) was administered during the challenges. Cellular infiltration into the lungs was analysed by flow cytometry. Airway remodelling was histologically evaluated. The following results were obtained. (1) Cell proliferation concomitant with a decrease in apoptotic cells was induced when ILC2s were cultured with TSLP and\/or IL\u20107, and was potently inhibited by dexamethasone. In contrast, when the culture with TSLP and IL\u20107 was performed in the presence of IL\u201033, the proliferative response exhibited steroid resistance. Steroid\u2010resistant ILC2 proliferation was suppressed by delgocitinib in a concentration\u2010dependent manner. (2) The culture with IL\u201033, TSLP, and IL\u20107 induced the overexpression of Bcl\u2010xL, which was clearly inhibited by delgocitinib, but not by dexamethasone. When ILC2s were treated with navitoclax, insensitivity to dexamethasone was significantly cancelled. (3) The development of airway remodelling and the infiltration of ILC2s into the lungs in the asthma model were not suppressed by dexamethasone, but were dose\u2010dependently inhibited by delgocitinib. Combination treatment with dexamethasone and either delgocitinib or navitoclax synergistically suppressed these responses. Therefore, JAKs appear to play significant roles in the induction of steroid resistance by up\u2010regulating Bcl\u2010xL in ILC2s. The inhibition of JAKs and Bcl\u2010xL has potential as pharmacotherapy for steroid\u2010resistant asthma, particularly that mediated by ILC2s.<\/jats:p>","DOI":"10.1111\/imm.13805","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T13:13:53Z","timestamp":1716556433000},"page":"653-668","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Involvement of <scp>Janus<\/scp> kinase\u2010dependent <scp>Bcl\u2010xL<\/scp> overexpression in steroid resistance of group 2 innate lymphoid cells in asthma"],"prefix":"10.1111","volume":"172","author":[{"given":"Hayato","family":"Shimora","sequence":"first","affiliation":[{"name":"Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences Setsunan University  Osaka 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