Friday, April 26, 2024
4/26/2024
Sepsis is an aberrant immune response to infection1 with approximately one million cases/year in the U.S.A. and an overall fatality rate of ~20-30%, increasing to ~40-50% in the case of septic shock1-3. Sepsis is characterized by stress hyperglycemia4, mitochondrial dysfunction5, and persistent, strongly oxidizing conditions. Although sepsis is a complex disease involving many different cells and tissues, a better understanding of the role of macrophages (Mf) during sepsis may reveal new therapeutic targets. Mf exhibit dynamic, stimulus-dependent functional plasticity in vitro and in vivo and critical changes to their activities during sepsis are thought to be initiated by bacterial products (e.g., lipopolysaccharide; LPS) and proinflammatory cytokines (e.g., interferon-g; IFN-g) that reprogram Mf to a highly proinflammatory, “classically activated” or “M1” phenotyperev. in 6. These signaling pathways also stabilize the transcription factor Hypoxia- Inducing Factor-1a (HIF-1a)7,8. HIF-1a is a master regulator of glycolytic genes9, facilitating a profound “metabolic switch,” the “Warburg effect” rev. in 10-12, in M1 Mf in which glycolysis predominates and mitochondrial oxidative phosphorylation is essentially absent, even when oxygen is present. We propose that this metabolic dysregulation underlies inflammation during sepsis, by driving production of proinflammatory cytokines as well as exposure of tissues to damaging M1 Mf-dependent reactive oxygen species (ROS), proteases, and bioactive lipids. While cytokines and ROS have been extensively studied, less is known about the role of methylglyoxal (MG), a highly reactive, dicarbonyl byproduct that can accumulate intracellularly during the glycolytic reaction mediated by triose phosphate isomerase (TPI)14,15. Significantly, elevated MG in sera of septic shock patients has been identified as a biomarker that correlates with disease severity21. We have reported that MG accumulates in M1 Mf upon stimulation with LPS and IFN-g in vitro, and results in the formation of covalent “MG-adducts” with host proteins both in vitro and in the lungs of endotoxic mice17. Our central hypothesis is that MG, a relatively short-lived, but highly reactive metabolite generated in response to LPS+IFN-g activation of Mf, directs inflammatory M1 Mf differentiation in sepsis, and that strategies that inhibit MG production or activity will prevent such differentiation, and thereby reduce Mf-directed inflammation. Our scientific premise is that selective targeting of MG accumulation can be capitalized upon to mitigate sepsis- associated tissue damage and death. We propose that LPS + IFN-g-induced stabilization of HIF-1a initiates sepsis by promoting M1 Mf differentiation through increased glycolysis, MG accumulation, MG-mediated glycation of mitochondrial proteins that disrupts mitochondrial function. Specific Aim 1 will characterize mechanisms by which MG accumulation in Mf disrupts mitochondrial function, Aim 2 will examine the role of metabolic signaling pathways on MG accumulation, and Aim 3 will test the therapeutic efficacy of MG- degrading enzymes to mitigate endotoxicity and bacterial sepsis.
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