NLRP3 Inflammasome: A Potential Alternative Therapy Target for Atherosclerosis

Abstract

Atherosclerosis (AS) is a complex and chronic inflammatory disease that occurs in multiple systems of the human body. It is an important pathological basis for a variety of diseases and a serious threat to human health. So far, many theories have been formed to explain the pathogenesis of atherosclerosis, among which “inflammation theory” has gradually become a research focus. This theory presents that inflammatory response runs through the whole progress of AS, inflammatory cells play as the main executors of AS, and inflammatory mediators are the key molecules of AS. In the inflammatory process of atherosclerosis, the role of NLRP3 in the atherosclerosis has gradually got the attention of researchers. NLRP3 is a kind of signal-transductional pattern recognition receptors (PRRs). After recognizing and binding to the damage factors, NLRP3 inflammasome will be assembled to activate IL-1β and caspase-1 pathways, resulting in promoting the inflammation process of AS, reducing the stability of the plaques, and finally increasing the incidence of adverse cardiovascular events. Taken above, the article will review the potential benefits of drugs targeting the NLRP3 inflammasome in the therapy of AS.

NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes

“…Liu et al reviewed the crucial role of NLRP3 in the pathogenesis of T2DM. It has been demonstrated that IL-1β is elevated in T2DM patients, suggesting that IL-1β may be linked with the development of T2DM [ 182 ]. Excessive IL-1β production in T2DM has a few consequences: (1) it induces the expression of other inflammatory mediators (IL-18, IL-33) using IL-1 receptor signaling that amplifies inflammatory reaction [ 183 ]; (2) it evokes oxidative stress as well as ER stress, which are both closely linked to T2DM [ 184 , 185 ]; and (3) it activates c-Jun N-terminal kinases (JNKs), inducing serine phosphorylation of insulin receptor substrate 1 (IRS-1) and attenuating the activity of the insulin-PI3K/AKT signaling pathway in insulin-sensitive tissues [ 186 ].…”

“…Hyperglycemia is one of the hallmarks of T2DM [ 207 ]. It has been known for almost two decades that the NLRP3 inflammasome is activated in response to high levels of glucose ( Figure 2 ) [ 182 , 208 ]. Some reports show that β cells in pancreatic islets produce IL-1β in response to high glucose, which contributes to glucotoxicity and results in functional impairment and apoptosis of β cells [ 58 ].…”

From Mitochondria to Atherosclerosis: The Inflammation Path

“…A direct NLRP3 inflammasome assembly inhibitor called CY-09 reduced inflammasome activation and shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes [ 224 ]. Nowadays, new approaches using natural compounds inhibiting NLRP3 inflammasome are also relevant [ 225 ], for example, artemisinin [ 226 ], rosmaniric acid [ 227 ], curcumin [ 228 ], and berberine [ 229 ]. In addition, the proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known protein for its role in the LDL-R homeostasis and atherosclerosis progression, was shown to have a pro-inflammatory effect in macrophages [ 230 ].…”

Atherosclerosis as Mitochondriopathy: Repositioning the Disease to Help Finding New Therapies

“…Mitochondria are involved in the initiation of NLRP3 assembly as the main ROS generators and sources of damaged mtDNA. It was shown that blocking mtROS formation inhibited the assembly of NLRP3 inflammasomes ( 65 ). In addition, mitochondrial damage was directly associated with NLRP3.…”