Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation

Unbalanced 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 hemato...

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Veröffentlicht in:Science advances 2021-05, Vol.7 (19)
Hauptverfasser: Virga, Federico, Cappellesso, Federica, Stijlemans, Benoit, Henze, Anne-Theres, Trotta, Rosa, Van Audenaerde, Jonas, Mirchandani, Ananda S, Sanchez-Garcia, Manuel A, Vandewalle, Jolien, Orso, Francesca, Riera-Domingo, Carla, Griffa, Alberto, Ivan, Cristina, Smits, Evelien, Laoui, Damya, Martelli, Fabio, Langouche, Lies, Van den Berghe, Greet, Feron, Olivier, Ghesquière, Bart, Prenen, Hans, Libert, Claude, Walmsley, Sarah R, Corbet, Cyril, Van Ginderachter, Jo A, Ivan, Mircea, Taverna, Daniela, Mazzone, Massimiliano
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Sprache:eng
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Zusammenfassung:Unbalanced 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abf0466