Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating JMJD3

Abstract

AbstractCholesterol plays an important role in regulating macrophage inflammatory responses, but the mechanism is poorly understood. Here we show that reducing cholesterol in macrophages by statins upregulates JMJD3, a H3K27me3 demethylase. We provide evidence that this upregulation involves altered mitochondrial function, particularly the ATP synthase in the inner mitochondrial membrane (IMM). ATP synthase is suppressed by statin due to reduced cholesterol levels in IMM. This promotes JMJD3 expression. We also demonstrate that reducing cholesterol in macrophages alters the epigenetic configuration or epigenome. When macrophages are classically activated (M1), statin treatment suppresses the pro-inflammatory phenotype while enhancing anti-inflammatory IL-10 expression. On the other hand, when macrophages are alternatively activated (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression of these anti-inflammatory factors correlates with H3K27me3 removal by statins in resting macrophages prior to activation. Lastly, we provide evidence that JMJD3 demethylase activity is necessary for cholesterol to modulate M1 and M2 activation in macrophages. We conclude that upregulation of JMJD3 in macrophages plays a key role in the anti-inflammatory effects of statins.Significance StatementIn addition to lowering the plasma LDL, statins exert a well-documented anti-inflammatory effect clinically, though the mechanism is unknown. We show here that, by decreasing cellular cholesterol content, statins reduce cholesterol in the IMM to upregulates JMJD3, which is essential for anti-inflammatory functions in macrophages. This novel mechanism may potentially operatein vivo. Bone-marrow derived cells, including macrophages, are highly proliferating and require plasma LDL and cholesterol biosynthesis to provide cholesterol for new membrane production. By lowering the plasma LDL and inhibiting HMG-CoA reductase, statin therapy could generate macrophages with relatively less cholesterol in membranes, including the IMM, thereby promoting JMJD3 expression and anti-inflammatory function. This could contribute at least in part to observed anti-inflammatory effects of statins in human population.