Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses

• 成果类型: Article
• 署名作者: Lesbats, Juliette; Brillac, Aurelia; Reisz, Julie A.; Mukherjee, Parnika; Lhuissier, Charlene; Fernandez-Monreal, Monica; Dupuy, Jean-William; Sequeira, Angele; Tioli, Gaia; de la Calle Arregui, Celia; Pinson, Benoit; Wendisch, Daniel; Rousseau, Benoit; Efeyan, Alejo; Sander, Leif Erik; D'Alessandro, Angelo; Garaude, Johan
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; University of Colorado System; University of Colorado Anschutz Medical Campus; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); Universite de Bordeaux; Universite de Bordeaux; University of Bologna; Centro Nacional de Investigaciones Oncologicas (CNIO); Universite de Bordeaux; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1180
• DOI: 10.1038/s41586-025-08629-4
• 发表日期: 2025-04-10
• 关键词: succinate-dehydrogenase; cell biology; amino-acids; metabolism; itaconate; mtorc1; metabolomics; activation; adaptations; maturation

摘要

Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1 beta secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.