Nur77 Deficiency Exacerbates Macrophage NLRP3 Inflammasome-Mediated Inflammation and Accelerates Atherosclerosis

Abstract

Purpose. Activation of NLR (nucleotide-binding and leucine-rich repeat immune receptor) family pyrin domain containing 3 (NLRP3) inflammasome mediating interleukin- (IL-) 1β secretion has emerged as an important component of inflammatory processes in atherogenesis. The nuclear receptor Nur77 is highly expressed in human atherosclerotic lesions; however, its functional role in macrophage NLRP3 inflammasome activation has not yet been clarified. Methods, Materials, and Results. Eight-week-old apolipoprotein E (ApoE)−/− and ApoE−/− Nur77−/− mice that were fed a Western diet underwent partial ligation of the left common carotid artery (LCCA) and left renal artery (LRA) to induce atherogenesis. Four weeks later, severe plaque burden associated with increased lipid deposition, reduced smooth muscle cells, macrophage infiltration, and decreased collagen expression was identified in ApoE−/− Nur77−/− mice compared with those in ApoE−/− mice. ApoE−/− Nur77−/− mice showed increased macrophage inflammatory responses in carotid atherosclerotic lesions. In vitro studies demonstrated that oxidized low-density lipoprotein cholesterol (ox-LDL) increased the release of lactate dehydrogenase (LDH) and upregulated the expressions of cleaved caspase-1, cleaved IL-1β and gasdermin D (GSMD) in WT peritoneal macrophages (PMs) in a NLRP3-dependent manner. Nur77−/− PMs exhibited a further increased level of NLRP3 inflammasome-mediated inflammation under ox-LDL treatment compared with WT PMs. Mechanistically, Nur77 could bind to the promoter of NLRP3 and inhibit its transcriptional activity. Conclusions. This study demonstrated that Nur77 deletion promotes atherogenesis by exacerbating NLRP3 inflammasome-mediated inflammation.

Nur77 is involved in the regulation of obesity‐related lower muscle mass by promoting Pten degradation

“…30,34 Interestingly, Nur77 protein levels decrease in liver and muscle tissue of mice fed an HFD. 35,36 Nur77 deficiency exacerbates lipid deposition in carotid arteries, liver, and skeletal muscle, [34][35][36] and deletion of Nur77 increases body fat mass in mice. 37,38 Thus, Nur77 is a regulator of obesity phenotype; however, whether it is involved in obesity-related lower muscle mass remains to be investigated.…”

“…Nur77 also regulates lipid metabolism by inhibiting fatty acid uptake in breast cancer and promoting lipolysis in skeletal muscle 31–33 . In addition, studies demonstrated that Nur77 deletion promotes lipid deposition by exacerbating inflammation 30,34 . Interestingly, Nur77 protein levels decrease in liver and muscle tissue of mice fed an HFD 35,36 .…”

“…[31][32][33] In addition, studies demonstrated that Nur77 deletion promotes lipid deposition by exacerbating inflammation. 30,34 Interestingly, Nur77 protein levels decrease in liver and muscle tissue of mice fed an HFD. 35,36 Nur77 deficiency exacerbates lipid deposition in carotid arteries, liver, and skeletal muscle, [34][35][36] and deletion of Nur77 increases body fat mass in mice.…”