Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Biomed Pharmacother. 2024 Oct;179:117431. doi: 10.1016/j.biopha.2024.117431. Epub 2024 Sep 10.
Skin psoriasis is defined as receiving external stimulation to activate skin dendritic cells (DCs) which can release interleukin 23 (IL-23) to interlink the innate and adaptive immunity as well as induce T helper 17 (Th17) cell differentiation leading to elevated production of interleukin 17 (IL-17) for keratinocytes over production. This autoimmune loop in psoriasis pathogenesis is influenced by G protein-coupled receptor (GPCR) signalling transduction, and in particular, function of adhesion molecule GPR97 in psoriasis endures to be utterly addressed. In this research, our team allocated GPR97 depletion (GPR97), GPR97 conditional depletion on dendritic cell (DC-cKO), and keratin 14-conditional knockout (K14-cKO) mice models to explore the function of GPR97 which influences keratinocytes and skin immunity. It was found that significantly aggravated psoriasis-like lesion in GPR97 mice. In addition, hyperproliferative keratinocytes as well as accumulation of DCs and Th17 cells were detected in imiquimod (IMQ)-induced GPR97 mice, which was consistent with the results in DC-cKO and K14-cKO psoriasis model. Additional investigations indicated that beclomethasone dipropionate (BDP), an agonist of GPR97, attenuated the psoriasis-like skin disease and restricted HaCaT cells abnormal proliferation as well as Th17 cells differentiation. Particularly, we found that level of NF-κB p65 was increased in GPR97 DCs and BDP could inhibit p65 activation in DCs. Role of GPR97 is indispensable and this adhesion receptor may affect immune cell enrichment and function in skin and alter keratinocytes proliferation as well as differentiation in psoriasis.
皮肤银屑病被定义为受到外部刺激，激活皮肤树突状细胞（DCs），这些细胞可以释放白细胞介素 23（IL-23），将先天免疫和适应性免疫联系起来，并诱导 T 辅助 17（Th17）细胞分化，导致角质形成细胞过度产生白细胞介素 17（IL-17）。银屑病发病机制中的这种自身免疫循环受到 G 蛋白偶联受体（GPCR）信号转导的影响，特别是粘附分子 GPR97 在银屑病中的作用仍有待完全阐明。在这项研究中，我们的团队分配了 GPR97 耗竭（GPR97）、树突状细胞（DC-cKO）条件性耗竭的 GPR97 和角蛋白 14 条件性敲除（K14-cKO）小鼠模型，以探索影响角质形成细胞和皮肤免疫的 GPR97 功能。结果发现，GPR97 小鼠的银屑病样病变明显加重。此外，在咪喹莫特（IMQ）诱导的 GPR97 小鼠中检测到过度增殖的角质形成细胞以及 DC 和 Th17 细胞的积累，这与 DC-cKO 和 K14-cKO 银屑病模型的结果一致。进一步的研究表明，GPR97 的激动剂倍氯米松二丙酸酯（BDP）减轻了银屑病样皮肤病，并限制了 HaCaT 细胞的异常增殖和 Th17 细胞的分化。特别是，我们发现 GPR97 DC 中的 NF-κB p65 水平增加，BDP 可以抑制 DC 中的 p65 激活。GPR97 的作用是不可或缺的，这种粘附受体可能会影响皮肤中免疫细胞的富集和功能，并改变银屑病中角质形成细胞的增殖和分化。
