The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages

Abstract

NLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE−/− mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE−/− mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE−/− mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1β and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

Zhilong Huoxue Tongyu Capsule Alleviated the Pyroptosis of Vascular Endothelial Cells Induced by ox-LDL through miR-30b-5p/NLRP3

“…Meanwhile miR-30b-5p has been implicated in activation of NLRP3 inflammasome in other studies [ 47 ]. Importantly, many research studies suggest that NLRP3 is involved in pyrophosis of AS [ 12 , 48 ]. Besides, ox-LDL induces the activation of NLRP3 inflammasome in the aorta [ 49 ], which is important for the formation of unstable plaques in AS by promoting Caspase 1 activation of cell pyroptosis involved in ox-LDL-induced apoptosis [ 48 ].…”

“…Importantly, many research studies suggest that NLRP3 is involved in pyrophosis of AS [ 12 , 48 ]. Besides, ox-LDL induces the activation of NLRP3 inflammasome in the aorta [ 49 ], which is important for the formation of unstable plaques in AS by promoting Caspase 1 activation of cell pyroptosis involved in ox-LDL-induced apoptosis [ 48 ]. Furthermore, miR-30b-5p is negatively correlated with NLRP3 [ 21 ], which was confirmed by our results including the dual-luciferase reporter gene system results and qRT-PCR results.…”

Pyroptosis-Mediated Periodontal Disease

“…In cardiovascular disease, disseminated periopathogens potentially causes the progression of atheroma lesions [ 83 ]. For example, caspase-11-gasdermin D-mediated pyroptosis and the subsequent pro-inflammatory response in macrophages are involved in the pathogenesis of atherosclerosis [ 117 ], and the selective NLRP3 inhibitor MCC950 hinders atherosclerosis development [ 118 ]. When focusing on rheumatoid arthritis, the disseminated P. gingivalis and A. actinomycetemcomitans may enhance pyroptosis of synovial cells [ 84 ].…”

Empagliflozin protects diabetic pancreatic tissue from damage by inhibiting the activation of the NLRP3/caspase-1/GSDMD pathway in pancreatic β cells: in vitro and in vivo studies

“…Previous studies have shown that NLRP3 is expressed in a variety of cells and its mediated signaling pathway plays an important role in the progression of diabetes [ 35 , 36 ]. Several studies have shown that activation of NLRP3 can stimulate inflammatory formation and pyroptosis of cells [ 37 , 38 ]. These findings prompted us to detect NLRP3 expression in db/db mice and analyze its association with pancreatic β cells.…”