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

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 [UCL] Ghesquière, Bart Prenen, Hans Libert, Claude Walmsley, Sarah R. Corbet, Cyril [UCL] Van Ginderachter, Jo A. Ivan, Mircea Taverna, Daniela Mazzone, Massimiliano et al.[show all]

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.