Department of Dermatology, School of Medicine, University of California San Diego, La Jolla, CA, United States.
Front Immunol. 2024 Sep 26;15:1469829. doi: 10.3389/fimmu.2024.1469829. eCollection 2024.
Psoriasis is an inflammatory skin condition where immune cells play a significant role. The importance of the cross-talk between keratinocytes and immune cells in the pathogenesis of psoriasis has recently been reaffirmed. Recent studies have found that several S1PR functional antagonists, other than S1PR2, are effective in improving psoriasis. This study aims to investigate the role of S1PR2 in psoriasis, that has not been investigated before.
Spatial transcriptomics, RT-qPCR, and flow cytometry were used to map the immune cell landscape and its association with metabolic pathways in an imiquimod (IMQ)-induced psoriasis-like inflammation in mice that could not sense sphingosine-1-phosphate (S1P) in the epidermis through the S1PR2 receptor.
Our analysis suggests that S1PR2 in keratinocytes plays a major role in psoriasis-like inflammation compared to other S1PRs. It acts as a down-regulator, inhibiting the recruitment of Th17 cells into the skin. In IMQ-induced psoriasis skin, both and mice showed higher expressions of proinflammatory cytokines such as TNF-α, IL-17A, and IL-1β together with higher expressions of MyD88/NF-κB pathway compared to the wild-type mice. Remarkably, in IMQ-treated mice, the deletion of in keratinocytes only resulted in a larger population of Th17 cells in skin-draining lymph nodes. Other S1PR modulators did not improve the worsening of psoriasis-like inflammation caused by S1PR2 deficiency in keratinocytes.
This study reaches two main conclusions: signals from keratinocytes play a central role in creating an immune environment that promotes the development of psoriasis, and stimulating S1PR2, instead of suppressing it, represents a potential therapeutic approach for psoriasis.
银屑病是一种炎症性皮肤病，其中免疫细胞起着重要作用。角质形成细胞与免疫细胞之间的串扰在银屑病发病机制中的重要性最近得到了再次证实。最近的研究发现，几种 S1PR 功能拮抗剂（除了 S1PR2 之外）在改善银屑病方面有效。本研究旨在研究以前尚未研究过的 S1PR2 在银屑病中的作用。
使用空间转录组学、RT-qPCR 和流式细胞术来绘制免疫细胞图谱及其与小鼠咪喹莫特（IMQ）诱导的银屑病样炎症中代谢途径的关联，这些小鼠由于表皮中的 S1PR2 受体无法感知鞘氨醇-1-磷酸（S1P）而无法感知 S1P。
我们的分析表明，与其他 S1PR 相比，角质形成细胞中的 S1PR2 在银屑病样炎症中起着主要作用。它作为下调因子，抑制 Th17 细胞向皮肤募集。在 IMQ 诱导的银屑病皮肤中，与野生型小鼠相比， 和 小鼠均表现出更高的促炎细胞因子（如 TNF-α、IL-17A 和 IL-1β）的表达，以及更高的 MyD88/NF-κB 通路表达。值得注意的是，在 IMQ 处理的小鼠中，角质形成细胞中 的缺失仅导致皮肤引流淋巴结中 Th17 细胞的数量增加。其他 S1PR 调节剂并不能改善角质形成细胞中 S1PR2 缺失引起的银屑病样炎症恶化。
本研究得出两个主要结论：来自角质形成细胞的信号在创造促进银屑病发展的免疫环境中起着核心作用，刺激 S1PR2（而不是抑制它）代表了一种潜在的银屑病治疗方法。
