Sting Regulates Metabolic Reprogramming In Macrophages Via Hif-1 Alpha During Brucella Infection

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-1 alpha), a global regulator of cellular metabolism and innate immune cell functions. HIF-1 alpha stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1 beta release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1 alpha 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-1 alpha stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1 alpha stabilization and IL-1 beta 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-1 alpha pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.Author summary The impact of host cell metabolism on pathogen growth or restriction represent an emerging field in immunology and shed light on the intricate network of signaling pathways during immune cells response. Here, we dissected a distinct mechanism by which STING regulates macrophage metabolic reprogramming eliciting an inflammatory profile during Brucella infection. Brucella abortus is an intracellular bacterium that causes brucellosis, an infectious disease that promotes abortion in domestic animals leading to severe economic losses and an inflammatory condition in humans. The metabolite reprogramming orchestrated by STING relies on HIF-1 alpha stabilization through increased succinate and mROS levels. We demonstrated that HIF-1 alpha stabilization enhances nitric oxide production, inflammasome activation and IL-1 beta release in infected macrophages, and this inflammatory profile participates in the control of bacterial replication. Thus, our findings bring new insights on this intricate circuit by which the host immune senses intracellular pathogens contributing to development of drugs and/or vaccines to control infectious diseases.