Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statinin vitroor from statin-treated mice, have reduced cholesterol levels and higher expression ofJmjd3,a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFκB andJmjd3expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statinsin vitroor isolated from statin-treated micein vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatoryIl10expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression ofArg1,Ym1, andMrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition,Jmjd3and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation ofJmjd3is a key event for the anti-inflammatory function of statins on macrophages.