CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes

• Published in: Research (Washington) Vol. 6; p. 0167
• Main Authors: Chen, Chao, Yi, Xiaoqing, Liu, Panpan, Li, Jie, Yan, Bei, Zhang, Detian, Zhu, Lei, Yu, Pian, Li, Lei, Zhang, Jiaxiong, Kuang, Yehong, Zhao, Shuang, Zhu, Wu, Peng, Cong, Chen, Xiang
• Format: Journal Article
• Language: English
• Published: United States AAAS 2023; American Association for the Advancement of Science (AAAS)
• ISSN: 2639-5274; 2639-5274
• DOI: 10.34133/research.0167

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/ ), 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- axis in the pathogenesis of psoriasis, indicating that epidermal CD147 is a promising target for psoriasis treatment.