CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes.
CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes.
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DOI：
10.34133/research.0167
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
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作者：
Chen C;Yi X;Liu P;Li J;Yan B;Zhang D;Zhu L;Yu P;Li L;Zhang J;Kuang Y;Zhao S;Zhu W;Peng C;Chen X
银屑病是一种慢性炎症性皮肤病，其特征是表皮细胞快速增殖。虽然糖酵解通量升高已被报道在银屑病，其发病机制的分子机制仍不清楚。我们研究了整合膜蛋白CD 147在银屑病发病机制中的作用，观察其在人类银屑病皮损和咪喹莫特（IMQ）诱导的小鼠模型中的高表达。在小鼠模型中，表皮CD 147的基因组缺失显著减弱了IMQ诱导的银屑病炎症。我们发现，CD 147与葡萄糖转运蛋白1（Glut 1）相互作用。表皮中CD 147的消耗在体外和体内阻断葡萄糖摄取和糖酵解。在CD 147敲除小鼠和角质形成细胞中，表皮中氧化磷酸化增加，表明CD 147在银屑病发病过程中糖酵解重编程中起关键作用。使用非靶向和靶向代谢技术，我们发现表皮CD 147缺失显著增加了肉毒碱和α-酮基谷氨酸（α-KG）的产生。CD 147的消耗还通过抑制H3 K9的组蛋白三甲基化来增加γ-丁酰甜菜碱羟化酶（γ-BBD/BBOX 1）的转录表达和活性，γ-丁酰甜菜碱羟化酶是肉毒碱代谢的关键分子。我们的研究结果表明，CD 147在银屑病发病机制中通过α-KG-H3 K9 me 3-BBOX 1轴的代谢重编程中至关重要，表明表皮CD 147是银屑病治疗的有希望的靶点。
Psoriasis is a chronic inflammatory skin disease featuring rapid proliferation of epidermal cells. Although elevated glycolysis flux has been reported in psoriasis, the molecular mechanisms underlying its pathogenesis remain unclear. We investigated the role of the integral membrane protein CD147 in psoriasis pathogenesis, observing its high expression in psoriatic skin lesions of humans and imiquimod (IMQ)-induced mouse models. In mouse models, genomic deletion of epidermal CD147 markedly attenuated IMQ-induced psoriatic inflammation. We found that CD147 interacted with glucose transporter 1 (Glut1). Depletion of CD147 in the epidermis blocked glucose uptake and glycolysis in vitro and in vivo. In CD147-knockout mice and keratinocytes, oxidative phosphorylation was increased in the epidermis, indicating CD147's pivotal role in glycolysis reprogramming during pathogenesis of psoriasis. Using non-targeted and targeted metabolic techniques, we found that epidermal deletion of CD147 significantly increased the production of carnitine and α-ketoglutaric acid (α-KG). Depletion of CD147 also increased transcriptional expression and activity of γ-butyrobetaine hydroxylase (γ-BBD/BBOX1), a crucial molecule for carnitine metabolism, by inhibiting histone trimethylations of H3K9. Our findings demonstrate that CD147 is critical in metabolic reprogramming through the α-KG–H3K9me3–BBOX1 axis in the pathogenesis of psoriasis, indicating that epidermal CD147 is a promising target for psoriasis treatment.