Macrophages play essential roles in defense against pathogen infection. Upon activation by inflammatory stimuli, these innate immune cells display a shift in energy utilization in favor of aerobic glycolysis with a diversion of pyruvate toward lactte production in lieu of further oxidation by mitochondria. Increased glucose uptake supports the acute anabolic needs of activated macrophages for functions including generation of free radical antimicrobial products, cytokine production, phagocytosis and motility. Many of these processes are controlled by Hif1?. While the adaptation in energy metabolism is essential to mount an effective pro- inflammatory response, this process also rapidly dampens mitochondrial respiration, which may lead to a progressive energy deficit. Consequently, increased macrophage dysfunction and death has been associated with severe sepsis and poor disease outcome in rodent models. Similarly, massive death of myeloid cell populations during sepsis is predictive of a fatal outcome in humans. Currently, little is known concerning mechanisms that restore mitochondrial metabolic function in inflammatory macrophages and whether this is necessary to limit inflammatory dysfunction. Preliminary results show that in the macrophage pro-inflammatory stimuli, such as acute LPS treatment or Ifn?-primed, chronic LPS challenge (or M1 activation), induce the expression of Bmal1, a master regulator of circadian rhythm. Using myeloid-specific Bmal1 knockout (M- Bmal1KO) mice, our results suggest that this resetting of the molecular clock following inflammatory stimulation facilitates the restoration of mitochondrial oxidative metabolism and cellular function. In addition, Bmal1 physically and functionally interacts with Hif1?. We will test the hypothesis that crosstalk between Bmal1 and Hif1? serves as a molecular switch that controls energy utilization from glycolytic to oxidative metabolism in inflammatory macrophages. Interestingly, both circadian regulation and Hif1? accumulation in peripheral tissues are dysregulated in obesity and with age. Therefore, results derived from the research plan may also have important implications in obesity- and age-related inflammatory dysfunction, including metabolic diseases.
Macrophages are innate immune cells that play essential roles in the initiation and resolution of inflammatory responses, processes that are energy demanding. This proposal will examine a new mechanism that controls metabolic adaptation to inflammatory stimuli to maintain energy homeostasis and proper cellular function in inflammatory macrophages. Results derived from this study have the potential to inform new therapeutic strategies for acute and chronic inflammatory diseases.
| Dai, Lingling; Bhargava, Prerna; Stanya, Kristopher J et al. (2017) Macrophage alternative activation confers protection against lipotoxicity-induced cell death. Mol Metab 6:1186-1197 |
