Details

Autor(en) / Beteiligte

• Gomes, Marco Tulio R
• Guimarães, Erika S
• Marinho, Fabio V
• Macedo, Isabella
• Aguiar, Eric R G R
• Barber, Glen N
• Moraes-Vieira, Pedro M M
• Alves-Filho, José Carlos
• Oliveira, Sergio C
• Tsolis, Renée M.

Titel

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection

Ist Teil von

• PLoS pathogens, 2021-05, Vol.17 (5), p.e1009597-e1009597

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2021

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.