A Murine Point Mutation of Sgpl1 Skin Is Enriched With Vγ6 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod Treatment.
A Murine Point Mutation of Sgpl1 Skin Is Enriched With Vγ6 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod Treatment.
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Sgpl1 皮肤的鼠点突变富含 Vγ6 IL17 产生细胞，并在咪喹莫特治疗后表现为色素沉着过度
DOI：
10.3389/fimmu.2022.728455
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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1-磷酸鞘氨醇裂解酶由 Sgpl1 基因编码，可降解 S1P，对于动物模型和人类中的 S1P 稳态至关重要。 S1P裂解酶缺乏的患者患有肾上腺功能不全、严重的淋巴细胞减少和皮肤病。在本研究中，我们使用随机诱变筛选来鉴定携带 Sgpl1 (M467K) 错义突变的小鼠品系。这种突变在多个器官中引起与Sgpl1敲除小鼠相似的病理，但极大地保留了其寿命，其中M467K突变小鼠在SPF条件下看起来正常，可存活40周以上，相比之下，敲除小鼠的寿命不超过6周。当用咪喹莫特治疗时，Sgpl1M467K 小鼠皮肤炎症加剧，表现为棘皮症和角化过度加剧。我们还证明，产生 IL17a 的 Vγ6+ 细胞在 Sgpl1M467K 皮肤中富集，并在咪喹莫特治疗后引起严重的病理。有趣的是，在咪喹莫特治疗一个月后，突变小鼠出现了增色斑块，而对照组则没有，这类似于 Sgpl1 缺陷患者中发现的皮肤病。因此，我们的结果表明，Sgpl1M467K点突变小鼠在接受咪喹莫特治疗后成功模拟了人类疾病。我们还揭示了皮肤中 γδT 细胞的一个主要亚群，分泌 IL17 的 Vγ6 T 细胞因 Sgpl1 缺陷而增强，并导致皮肤病理学。因此，我们首次将 IL17a 和 γδT 细胞与 SPL 不足联系起来。
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, Sgpl1M467K mice experienced exacerbated skin inflammation, as revealed by aggravated acanthosis and orthokeratotic hyperkeratosis. We also demonstrated that the IL17a producing Vγ6+ cell was enriched in Sgpl1M467K 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 Sgpl1M467K point mutation mice successfully modeled a human disease after being treated with Imiquimod. We also revealed a major subset of γδT cells in the skin, IL17 secreting Vγ6 T cells were augmented by Sgpl1 deficiency and led to skin pathology. Therefore, we have, for the first time, linked the IL17a and γδT cells to SPL insufficiency.