Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes

作者：S. Nobs, Aleksandra A. Kolodziejczyk, Lital Adler, N. Horesh, Christine Botscharnikow, Elizabeth Herzog, Gayatree Mohapatra, Sophia Hejndorf, R. Hodgetts, Igor Spivak, Lena Schorr, Leviel Fluhr, Denise Kviatcovsky, A. Zacharia, Suzanne Njuki, D. Barasch, Noa Stettner, Mally Dori-Bachash, A. Harmelin, Alexander Brandis, Tevie Mehlman, A. Erez, Yiming He, S. Ferrini, Jens Puschhof, Hagit Shapiro, M. Kopf, A. Moussaieff, Suhaib K. Abdeen, E. Elinav · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06803-0 · 被引用次数：77 · 研究领域：Medicine

Hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ^ 1 ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in inf...