Biology subjects

Zabalawi, M.

Publications and source records attributed to Zabalawi, M..

3 recordsLinked to original sources

bioRxiv2021

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Activating macrophage NLRP3 inflammasome can promote excessive inflammation, with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and IL-1{beta} secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves cristae ultrastructure, and attenuates mitochondrial ROS production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. We suggest that PDHK inhibition improves mitochondrial fitness by reversing NLRP3 inflammasome activation in acutely inflamed macrophages.

immunology↗

bioRxiv2021

Hematopoietic-SLC37A2 deficiency impairs M2 macrophage polarization and accelerates atherosclerosis in LDL receptor-deficient mice

Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr-/- mice by bone marrow transplantation. Hematopoietic-specific SLC37A2 deletion in Ldlr-/- mice increased plasma lipid concentrations 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr-/- mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions.

immunology↗

bioRxiv2021

Dichloroacetate improves systemic energy balance and feeding behavior during sepsis

Sepsis is a life-threatening organ dysfunction by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism wide hyper-inflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprograming at organ levels remains unknown. We analyzed substrate utilization by the respiratory exchange ratio, energy expenditure, metabolomic screening and transcriptional profiling in a cecal ligation and puncture (CLP) model, to show that sepsis increases circulating free fatty acids and acylcarnitines but decreases levels of amino acids and carbohydrates leading to a drastic shift in systemic fuel preference. Comparative analysis of previously published metabolomics from septic liver indicates a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of both plasma and the liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggests that the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Interestingly, intraperitoneal injection of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses sepsis-induced anorexia, energy imbalance, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicate that PDK inhibition rescues systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.

immunology↗