美国纽约大学Shruti Naik等研究人员合作发现，皮肤上皮与17型免疫之间的代谢协调可维持慢性皮肤炎症。该研究于2024年5月20日在线发表于国际一流学术期刊《免疫》。

研究人员表明，单细胞和空间转录组学（ST）以及免疫荧光发现，IL-17信号下游的缺氧诱导因子1α（HIF1α）驱动了银屑病上皮的重塑。体内阻断人类银屑病皮损中的HIF1α会损害糖酵解，并与抗IL-17疗法相仿。在小鼠皮肤炎症模型中，表皮特异性缺失HIF1α或其靶基因葡萄糖转运体1可改善表皮、免疫、血管和神经元病理学。

从机理上讲，糖酵解自发地促进了上皮病理变化并增强了乳酸的产生，从而增强了γδ T17细胞的反应。RORγt驱动的基因缺失或药物抑制乳酸生成酶或乳酸转运体可减轻上皮病理变化和体内IL-17A的表达。这些研究结果确定了上皮细胞和免疫细胞之间的代谢层级，以及由此产生的维持炎症性疾病的代谢过程的协调。

据悉，免疫细胞和上皮细胞同时失调会引发炎症性上皮疾病。目前还不清楚这两个失调的细胞区如何同时维持它们的高代谢需求。

附：英文原文

Title: Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation

Author: Ipsita Subudhi, Piotr Konieczny, Aleksandr Prystupa, Rochelle L. Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine P. Lu, Niroshana Anandasabapathy, Mayte Suárez-Farias, Johann E. Gudjonsson, Aristotelis Tsirigos, Jose U. Scher, Shruti Naik

Issue&Volume: 2024-05-20

Abstract: Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immuneand epithelial cells. How these two dysregulated cellular compartments simultaneouslysustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics(ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α),downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1αin human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skininflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically,glycolysis autonomously fueled epithelial pathology and enhanced lactate production,which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacologicalinhibition of either lactate-producing enzymes or lactate transporters attenuatedepithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartmentsand the consequent coordination of metabolic processes that sustain inflammatory disease.

DOI: 10.1016/j.immuni.2024.04.022

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00227-9