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As aberrant inflammasome activation occurs in autoimmune disorders including Sj\u00f6gren\u2019s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1\u03b1 injection. Chronic inflammation was studied using two Sj\u00f6gren\u2019s syndrome models: diseased NOD.H2b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1-\/-) compared to TSP-1WT\u00a0C57BL\/6J mice. Inflammasome activation was investigated by immunostaining using the R26ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS\/Nigericin, IL-1\u03b1 and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1\/4, and interleukins Il1b and Il18. We also found increased IL-1\u03b2 maturation in Sj\u00f6gren\u2019s syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2b lacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPAR\u03b1)\/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sj\u00f6gren\u2019s syndrome-like pathogenesis in the NOD.H2b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.<\/jats:p>","DOI":"10.3390\/ijms24054309","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T03:32:17Z","timestamp":1677036737000},"page":"4309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-9698","authenticated-orcid":false,"given":"Vanessa","family":"Delcroix","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-5025","authenticated-orcid":false,"given":"Olivier","family":"Mauduit","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-7194","authenticated-orcid":false,"given":"Menglu","family":"Yang","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7818-3252","authenticated-orcid":false,"given":"Amrita","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Umazume","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-5494","authenticated-orcid":false,"given":"Cintia S.","family":"de Paiva","sequence":"additional","affiliation":[{"name":"The Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valery I.","family":"Shestopalov","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlene A.","family":"Dartt","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute\/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen P.","family":"Makarenkova","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S1542-0124(12)70148-9","article-title":"Inflammation in dry eye","volume":"2","author":"Stern","year":"2004","journal-title":"Ocul. 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