Virga, FedericoCappellesso, FedericaStijlemans, BenoitHenze, Anne-TheresTrotta, RosaVan Audenaerde, JonasMirchandani, Ananda S.Sanchez-Garcia, Manuel A.Vandewalle, JolienOrso, FrancescaRiera-Domingo, CarlaGriffa, AlbertoIvan, CristinaSmits, EvelienLaoui, DamyaMartelli, FabioLangouche, LiesVan den Berghe, GreetFeron, OlivierGhesquière, BartPrenen, HansLibert, ClaudeWalmsley, Sarah R.Corbet, CyrilVan Ginderachter, Jo A.Ivan, MirceaTaverna, DanielaMazzone, Massimiliano2024-03-262024-03-262021-05-07Virga F, Cappellesso F, Stijlemans B, et al. Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation. Sci Adv. 2021;7(19):eabf0466. Published 2021 May 7. doi:10.1126/sciadv.abf0466https://hdl.handle.net/1805/39534Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.en-USAttribution-NonCommercial 4.0 InternationalInflammationMacrophagesMicroRNAsSepsisArticle