Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation
Federico Virga, Federica Cappellesso, Benoı̂t Stijlemans, Anne‐Theres Henze, Rosa Trotta, Jonas R.M. Van Audenaerde, Ananda S. Mirchandani, Manuel A. Sánchez-García, Jolien Vandewalle, Francesca Orso, Carla Riera‐Domingo, Alberto Griffa, Cristina Ivan, Evelien Smits, Damya Laoui, Fabio Martelli, Lies Langouche, Greet Van den Berghe, Olivier Féron, Bart Ghesquière, Hans Prenen, Claude Libert, Sarah R. Walmsley, Cyril Corbet, Jo A. Van Ginderachter, Mircea Ivan, Daniela Taverna, Massimiliano Mazzone
Abstract
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.