P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation

Abstract

Purinergic 2X7 receptor (P2X7R) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE−/− mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1β expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE−/− mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE−/− mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation.

PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

“…Lu et al 7 first showed that EIF2AK2 is required for inflammasome activation, whereas He et al 32 first suggested that EIF2AK2 is not required for inflammasome activation. Now many different groups support that EIF2AK2 contributes to inflammasome activation3334353637, although few studies still dispute the function of EIF2AK2 in inflammasome activation38. Thus, context-dependent cell signalling may play an important role in the regulation of EIF2AK2-mediated inflammasome activation.…”

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

“…1). In response to harmful lipids such as palmitate and oxidized cholesterol, PKR can activate JNK, leading to engagement of downstream transcription factor activator protein 1 (AP-1) and expression of genes that mediate inflammation and apoptosis and promote inflammasome activity (32)(33)(34). It is unlikely that a single receptor or molecular event underlies these lipotoxic responses; however, it is possible to envision common signaling intermediates that mediate the vast array of downstream biological outcomes of lipotoxicity.…”

Activation of the CXCL16/CXCR6 Pathway by Inflammation Contributes to Atherosclerosis in Patients with End-stage Renal Disease

“…Piscopiello et al 26 first reported expression of P2X7R on human vessels and suggested a role for P2X7R in atherosclerosis. Furthermore, Peng et al 27 recently showed that P2X7R exacerbated atherosclerosis by promoting NLRP3 inflammasome activation. Therefore, P2X7R is believed to participate in lipid accumulation primarily through its inflammatory phenotype.…”