A Murine Point Mutation of Sgpl1 Skin Is Enriched With Vγ6 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod Treatment

Sphingosine-1-phosphate lyase is encoded by the Sgpl1 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 Sgpl1 (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, Sgpl1(M467K) mice experienced exacerbated skin inflammation, as revealed by aggravated acanthosis and orthokeratotic hyperkeratosis. We also demonstrated that the IL17a producing V gamma 6(+) cell was enriched in Sgpl1(M467K) 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 Sgpl1 deficient patients. Therefore, our results demonstrate that Sgpl1(M467K) point mutation mice successfully modeled a human disease after being treated with Imiquimod. We also revealed a major subset of gamma delta T cells in the skin, IL17 secreting V gamma 6 T cells were augmented by Sgpl1 deficiency and led to skin pathology. Therefore, we have, for the first time, linked the IL17a and gamma delta T cells to SPL insufficiency.

Automated summary

This study identified a mouse line carrying a missense mutation of Sgpl1, which successfully modeled a human disease after treatment with Imiquimod. The mutation caused similar pathologies as Sgpl1 knock-out mice in multiple organs but greatly preserved the lifespan. The study also revealed an enrichment of IL17a producing V gamma 6(+) cells in the skin, which contributed to severe skin pathology.