Abstract
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−/− background by bone marrow transplantation. Hematopoietic cell-specific SLC37A2 deletion in Ldlr−/− mice increased plasma lipid concentrations after 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.
Highlights
Atherosclerosis is driven by hyperlipidemia and exacerbated by chronic low-grade inflammation [1,2,3,4,5,6]
We previously showed that SLC372 is a novel regulator of macrophage inflammation by controlling glycolysis [24]
We found that hematopoietic SLC37A2deficient mice showed a 51% increase in aortic root lesions stained with Oil Red O (Figures 4A,B), despite similar CD68 (Figures 4C,D), suggesting that hematopoietic solute carrier family 37 member 2 (SLC37A2) deletion accelerates atherosclerotic plaque formation but has no effect on macrophage content
Summary
Atherosclerosis is driven by hyperlipidemia and exacerbated by chronic low-grade inflammation [1,2,3,4,5,6]. The anti-inflammatory (M2) macrophages can be subdivided into M2a, 2b, 2c, and 2d based on the stimuli and resultant transcriptional changes [11]. These in vitro models of macrophage polarization (M1 vs M2) are more simplified than the microenvironment that macrophages encounter in an atherosclerotic lesion [12]. Mounting evidence suggests that macrophage plasticity or phenotypic switch impacts atherosclerotic lesion progression and regression [1, 13, 14]. Uncovering the underlying mechanisms governing activation and deactivation of macrophages and their phenotypic switch provides a promising avenue to prevent and treat atherosclerosis
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