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We show that esophageal epithelial cells and macrophage-derived NLRP3 regulated IL-18 initiate the disease and induced IL-5 facilitates eosinophil growth and survival. We also found that <jats:italic>A. fumigatus<\/jats:italic>-exposed IL-18<jats:sup>\u2212\/\u2212<\/jats:sup> mice or IL-18-neutralized mice are protected from EoE induction. Most importantly, we present that intravascular rIL-18 delivery to \u0394dblGATA mice and CD2-IL-5 mice show the development of EoE characteristics feature like degranulated and intraepithelial eosinophils, basal cell hyperplasia, remodeling and fibrosis. Similarly, we show an induced NLRP3-caspase1-regulated IL-18 pathway is also operational in human EoE. Lastly, we present the evidence that inhibitors of NLRP3 and caspase-1 (MCC950, BHB, and VX-765) protect <jats:italic>A. fumigatus<\/jats:italic>- and corn-extract-induced EoE pathogenesis. In conclusion, the current study provides a new understanding by implicating NLRP3\/caspase1-regulated IL-18 pathway in EoE pathogenesis. The study has the clinical significance and novel therapeutic strategy, which depletes only IL-18-responsive pathogenic eosinophils, not na\u00efve IL-5-generated eosinophils critical for maintaining innate immunity.<\/jats:p>","DOI":"10.1038\/s42003-023-05130-4","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T10:01:52Z","timestamp":1690797712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Allergen-induced NLRP3\/caspase1\/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis"],"prefix":"10.1038","volume":"6","author":[{"given":"Chandra Sekhar","family":"Yadavalli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathisha","family":"Upparahalli Venkateshaiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemanth Kumar","family":"Kandikattu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lokanatha","family":"Oruganti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra Sekhar","family":"Kathera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-4684","authenticated-orcid":false,"given":"Anil","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,31]]},"reference":[{"key":"5130_CR1","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/S0065-2776(01)78007-8","volume":"78","author":"ME Rothenberg","year":"2001","unstructured":"Rothenberg, M. 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However, A.M. filed a patent to protect using humanized antagonist or anti-antibody of NLRP3-Caspase1-IL-18 for targeting human eosinophils associated disease pathogenesis.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"763"}}