Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.
Federico VirgaFederica CappellessoBenoît StijlemansAnne-Theres HenzeRosa TrottaJonas R M Van AudenaerdeAnanda S MirchandaniManuel A Sanchez-GarciaJolien VandewalleFrancesca OrsoCarla Riera-DomingoAlberto GriffaCristina IvanEvelien L J SmitsDamya LaouiFabio MartelliLies LangoucheGreet Van den BergheOlivier FeronBart GhesquiereHans PrenenClaude LibertSarah R WalmsleyCyril CorbetJo A Van GinderachterMircea IvanDaniela TavernaMassimilliano MazzonePublished in: Science advances (2021)
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.
Keyphrases
- cell proliferation
- long non coding rna
- long noncoding rna
- dendritic cells
- immune response
- oxidative stress
- acute kidney injury
- intensive care unit
- candida albicans
- transcription factor
- coronary artery disease
- machine learning
- peripheral blood
- skeletal muscle
- cardiovascular events
- electronic health record
- data analysis
- endoplasmic reticulum
- single cell
- lps induced
- antimicrobial resistance
- high fat diet induced
- virtual reality