{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:57:13Z","timestamp":1753891033472,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014220","name":"National Natural Science Foundation of China-Henan Joint Fund","doi-asserted-by":"publisher","award":["U1904157"],"award-info":[{"award-number":["U1904157"]}],"id":[{"id":"10.13039\/501100014220","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sphingosine-1-phosphate lyase is encoded by the <jats:italic>Sgpl1<\/jats:italic> gene, degrades S1P, and is crucial for S1P homeostasis in animal models and humans. S1P lyase deficient patients suffer from adrenal insufficiency, severe lymphopenia, and skin disorders. In this study, we used random mutagenesis screening to identify a mouse line carrying a missense mutation of <jats:italic>Sgpl1<\/jats:italic> (M467K). This mutation caused similar pathologies as Sgpl1 knock-out mice in multiple organs, but greatly preserved its lifespan, which M467K mutation mice look normal under SPF conditions for over 40 weeks, in contrast, the knock-out mice live no more than 6 weeks. When treated with Imiquimod, <jats:italic>Sgpl1<\/jats:italic><jats:sup>M467K<\/jats:sup> mice experienced exacerbated skin inflammation, as revealed by aggravated acanthosis and orthokeratotic hyperkeratosis. We also demonstrated that the IL17a producing V\u03b36<jats:sup>+<\/jats:sup> cell was enriched in <jats:italic>Sgpl1<\/jats:italic><jats:sup>M467K<\/jats:sup> skin and caused severe pathology after imiquimod treatment. Interestingly, hyperchromic plaque occurred in the mutant mice one month after Imiquimod treatment but not in the controls, which resembled the skin disorder found in <jats:italic>Sgpl1<\/jats:italic> deficient patients. Therefore, our results demonstrate that <jats:italic>Sgpl1<jats:sup>M467K<\/jats:sup><\/jats:italic> point mutation mice successfully modeled a human disease after being treated with Imiquimod. We also revealed a major subset of \u03b3\u03b4T cells in the skin, IL17 secreting V\u03b36 T cells were augmented by <jats:italic>Sgpl1<\/jats:italic> deficiency and led to skin pathology. Therefore, we have, for the first time, linked the IL17a and \u03b3\u03b4T cells to SPL insufficiency.<\/jats:p>","DOI":"10.3389\/fimmu.2022.728455","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T06:05:56Z","timestamp":1655100356000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A Murine Point Mutation of Sgpl1 Skin Is Enriched With V\u03b36 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod 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