Abstract
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.
Highlights
Over the past decade, immunometabolism, or how changes in metabolic processes regulate immune cell responses, gained appreciation and is recognized as a rising field in immunology [1]
We dissected a distinct mechanism by which stimulator of interferon genes (STING) regulates macrophage metabolic reprogramming eliciting an inflammatory profile during Brucella infection
We demonstrated that hypoxia-inducible factor 1α (HIF-1α) stabilization enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages, and this inflammatory profile participates in the control of bacterial replication
Summary
Immunometabolism, or how changes in metabolic processes regulate immune cell responses, gained appreciation and is recognized as a rising field in immunology [1]. Of particular interest is the metabolic reprogramming of macrophages, i.e. the key metabolic and functional differences between the so-called M1- and M2-like macrophages, a polarized simplified model for a reality of much greater dynamism and complexity, commonly associated with an inflammatory or anti-inflammatory status, respectively [2] In this regard, the M1-like macrophage profile is characterized by the production of inflammatory cytokines, such as IL-1β, by nitric oxide (NO) production through inducible nitric oxide synthase (NOS2), and by efficient generation of reactive oxygen species (ROS) [2]. Extracellular succinate can activate its cognate receptor SUCNR1/GPR91 (G protein–coupled receptor 91) that acts in synergy with TLR ligands, driving inflammatory cytokine production [12] Due to this set of features, M1-like macrophages are considered as inflammatory and display enhanced antimicrobial activity [2]. M2-like macrophages are associated with the generation of anti-inflammatory
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
