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 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. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Citation

Federico Virga, Federica Cappellesso, Benoit Stijlemans, Anne-Theres Henze, Rosa Trotta, Jonas Van Audenaerde, Ananda S Mirchandani, Manuel A Sanchez-Garcia, Jolien Vandewalle, Francesca Orso, Carla Riera-Domingo, Alberto Griffa, Cristina Ivan, Evelien Smits, Damya Laoui, Fabio Martelli, Lies Langouche, Greet Van den Berghe, Olivier Feron, Bart Ghesquière, Hans Prenen, Claude Libert, Sarah R Walmsley, Cyril Corbet, Jo A Van Ginderachter, Mircea Ivan, Daniela Taverna, Massimiliano Mazzone. Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation. Science advances. 2021 May;7(19)

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PMID: 33962944

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