| 著者 |
Davanzo GG, Ribeiro G, Dos-Santos D, Berçot MR, Zaidan I, Menezes Dos Reis L, Virgilio-da-Silva JV, Castelucci BG, Estevão P, Souza WD, Bruneta HS, Fachi JL, Costa WL, Andrade JNB, Profeta GS, Dias RR, Wassano NS, de Brito Monteiro L, Aparecida da Silva Pereira J, Favero de Aguiar C, Cruz Angelim MKS, Santos WG, Carregari VC, Peña J, de Carvalho Fraga CA, Mori MA, Consonni SR, Martins-de-Souza D, Vinolo MAR, Nakaya H, Murray PJ, Beheshti A, Cunha LD, Moraes-Vieira PM.
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| Abstract |
Hypoxia-inducible factor 1α (HIF-1α) broadly orchestrates metabolic reprogramming in inflammatory macrophages. However, how HIF-1α shapes the earliest events following activation of pattern recognition receptors and triggers inflammatory responses remain unclear. We found that HIF-1α is functionally active shortly after macrophage inflammatory stimulation via a Rubicon (RUBCN)-NADPH oxidase (NOX2) reactive oxygen species (ROS) circuit, driving glycolysis, cytokine production, and bacterial killing before maximal protein accumulation. Early HIF-1α stabilization primes inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, which subsequently suppresses electron transport chain function and induces mitochondrial dysfunction independently of RUBCN and NOX2. These findings elucidate a temporally coordinated HIF-1α pathway that integrates RUBCN-NOX2 redox signaling to control macrophage inflammation, metabolic adaptation, and antimicrobial defense.
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