Sestrin1 inhibits oxidized low‐density lipoprotein‐induced activation of NLRP3 inflammasome in macrophages in a murine atherosclerosis model

• Published in: European journal of immunology 2020-08, Vol.50 (8), p.1154-1166
• Main Authors: Keping, Yang, Yunfeng, Sun, Pengzhuo, Xiao, Liang, Li, Chenhong, Xu, Jinghua, Mao
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Aorta; Aortitis - etiology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - etiology; Caspase; Cell activation; Cell Cycle Proteins - physiology; Cholesterol; Coronary vessels; Cytokines; Disease Models, Animal; Inflammasomes; Inflammasomes - physiology; Inflammation; Lipopolysaccharides; Lipoproteins; Lipoproteins, LDL - antagonists & inhibitors; Macrophages; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; NF-kappa B - physiology; NLR Family, Pyrin Domain-Containing 3 Protein - physiology; NLRP3; Sestrin1; Signal Transduction - physiology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201948427

Macrophages play a crucial role in the progression of atherosclerotic lesions. In the current study, we analyzed the expression and function of sestrin1 (SESN1) in the aorta macrophages in a murine atherosclerosis model. We identified high SESN1 expression in the aorta macrophages in atherosclerotic mice. Using lentivirus‐mediated SESN1 overexpression in macrophages, we found that SESN1 inhibited oxidized low‐density lipoprotein–induced NLRP3 inflammasome activation in lipopolysaccharide (LPS)‐primed macrophages, as evidenced by less ASC‐NLRP3 complex formation, lower caspase‐1 activation, and lower generation of mature IL‐1β. Besides, SESN1 impeded oxidized low‐density lipoprotein–induced activation of NK‐κB signaling in macrophages. Furthermore, SESN1 suppressed cholesterol crystal‐induced NLRP3 inflammasome activation and foam cell formation. Adoptive transfer of SESN1 overexpressing macrophages reduced the expression of pro‐inflammatory cytokines in infiltrating macrophages and the whole aorta tissue. Adoptive transfer of SESN1 knockdown macrophages enhanced the expression of pro‐inflammatory cytokines in infiltrating macrophages and the whole aorta tissue. Overall, our study sheds light on the significance of SESN1 for macrophage‐mediated aorta inflammation. Through in vivo and in vitro analysis, we unveiled the role or sestrin1 in the suppression of oxidized low‐density lipoprotein‐induced NLRP3 inflammasome formation and subsequent inflammatory response in macrophages in an atherosclerotic model. Our data provide insight into the pathophysiology of atherosclerosis.