TOMM40 Knockdown in Macrophages Inhibits Oxidized LDL-induced NLRP3 Activation and Promotes LXR-β Mediated Cholesterol Transporter Gene Expression

Abstract

Atherogenesis has been shown in mice to be dependent on activation of the NLRP3 inflammasome, a cytosolic innate immune sensor activated by a broad range of pathogen and damage associated molecular patterns, including oxidized LDL (oxLDL) in atherosclerosis. Previous work from our group has shown that knockdown of Translocase of Outer Mitochondrial Membrane 40 (TOMM40), which encodes a component of the mitochondrial importer TOM complex, increases expression and activity of the nuclear receptor-family transcription factor, liver X receptor (LXR) in hepatocytes. As LXR agonists have been shown to inhibit NLRP3 activation, we confirmed the prediction that TOMM40 knockdown has this effect in THP-1 monocyte-derived macrophages. Further, we demonstrated that TOMM40 KD upregulates LXR-mediated macrophage expression of the ABCA1 and ABCG1 genes which encode transporters that promote cellular cholesterol efflux, the first step in reverse cholesterol transport to the liver. Taken together, these findings identify a novel mechanism whereby increased LXR activity induced by suppression of TOMM40 expression in macrophages may retard atherogenesis both by inhibiting inflammation and promoting reverse cholesterol transport.