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.

• Authors: Ruosen Yuan, Weifeng Zhang, Peng Nie, Keke Lan, Xiaoxiao Yang, Anwen Yin, Qingqing Xiao, Yejiao Shen, Ke Xu, Xia Wang, Xin Pan, Linghong Shen, Ben He
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2022 Pg. 2017815 ( 2022) ISSN: 1942-0994 [Electronic] United States
• PMID: 35464766 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Ruosen Yuan et al.

Chemical References

• Apolipoproteins E
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nr4a1 protein, mouse
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Cholesterol

Topics

• Animals
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (pathology)
• Cholesterol (metabolism)
• Inflammasomes (metabolism)
• Inflammation (pathology)
• Interleukin-1beta (metabolism)
• Macrophages (metabolism)
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Nuclear Receptor Subfamily 4, Group A, Member 1