GPCRs in NLRP3 Inflammasome Activation, Regulation, and Therapeutics

Multiple ions, metabolites, hormones, and neurotransmitters regulate NLRP3 inflammasome activation through GPCRs. GPCRs facilitate NLRP3 inflammasome activation by increasing NLRP3 expression or regulating ion fluxes and mtROS production. GPCRs inhibit NLRP3 inflammasome activation by different signaling pathways, including transcriptional repression, post-translational modification and autophagy-dependent degradation. Targeting GPCRs may be effective for the clinical treatment of NLRP3-driven diseases. The NLRP3 inflammasome is an intracellular multimeric protein complex which plays an important role in the pathogenesis of various human inflammatory diseases, such as diabetes, Alzheimer's disease and atherosclerosis. Recently, various G protein-coupled receptors (GPCRs) have been reported to be involved in the activation and regulation of the NLRP3 inflammasome by sensing multiple ions, metabolites, and neurotransmitters, suggesting GPCR signaling is an important regulator for NLRP3 inflammasome. Here, we will review how various GPCRs promote or inhibit NLRP3 inflammasome activation and discuss the implications of GPCRs as drug targets for the therapy of NLRP3-driven diseases. The NLRP3 inflammasome is an intracellular multimeric protein complex which plays an important role in the pathogenesis of various human inflammatory diseases, such as diabetes, Alzheimer's disease and atherosclerosis. Recently, various G protein-coupled receptors (GPCRs) have been reported to be involved in the activation and regulation of the NLRP3 inflammasome by sensing multiple ions, metabolites, and neurotransmitters, suggesting GPCR signaling is an important regulator for NLRP3 inflammasome. Here, we will review how various GPCRs promote or inhibit NLRP3 inflammasome activation and discuss the implications of GPCRs as drug targets for the therapy of NLRP3-driven diseases. an enzyme that catalyzes the cyclization of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). It is dually regulated by different GPCRs (Gαs and Gαi-linked GPCRs stimulates and inhibits its activity respectively). functionally selective ligands that can preferentially activate some but not all receptor-linked signaling pathways. This offers a new mechanism for reducing drug side effects. steroid acids found predominantly in the bile of mammals, which facilitate the digestion and absorption of dietary lipids. These also act as hormones to induce metabolic effects through two specific receptors, the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5). a ubiquitous second messenger that is synthesized from ATP by adenylate cyclase (ADCY) and inactivated by hydrolysis to AMP by phosphodiesterase. This molecule mediates various cellular processes by activating downstream effectors, including protein kinase A (PKA), exchange proteins directly activated by cAMP (EPACs), and ion channels. host metabolic products or environmental agonists, such as monosodium urate (MSU), amyloid-β, cholesterol crystals, and silica, that can initiate a noninfectious inflammatory response. two important second messengers, which are produced by GPCRs excitation, phospholipase C (PLC) activation, and phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis. After hydrolysis of PIP2, the soluble IP3 binds to a receptor on the ER (IP3R), inducing the release of Ca2+ into the cytosol while DAG remains in the inner layer of the plasma membrane, recruits and activates PKC. Both released Ca2+ and activated PKC can then promote numerous downstream signaling pathways. numerous metabolic products (such as monosodium urate crystals, cholesterol crystals, and ATP), environmental irritants (such as asbestos and silica), and microbial molecules (such as viral RNA, nigericin) act as agonists to induce NLRP3 inflammasome activation. Among these stimuli, particulate matters, such as silica and monosodium urate, act as slow-acting agonists to activate the NLRP3 inflammasome after several hours through a phagocytic pathway. In contrast, ATP and nigericin are fast-acting agonists that can induce NLRP3 inflammasome activation within 0.5 hours. polyunsaturated fatty acids, in which the first double bond is between the third and fourth carbon atoms from the methyl (-CH3) end. They exhibit potential anti-inflammatory activity and protect against a variety of inflammatory human diseases, such as diabetes, atherosclerosis, and arthritis. conserved molecules derived from microbes that can initiate the innate immune response through the activation of innate immune sensors. a gasdermin D (GSDMD)-dependent programmed cell death, which is initiated by caspase-1 or caspase-11 activation. It occurs most frequently on infection with intracellular pathogens. fatty acids with two to six carbon atoms, which are produced by dietary fiber fermentation in the colon. They play an important role in colon health and reduce the risk of various inflammatory diseases, such as type 2 diabetes, obesity, and inflammatory bowel disease. endogenous or environmental DAMPs (such as cholesterol, MSU, and asbestos)-induced inflammation, which plays a key role in the development of various acute and chronic diseases, such as ischemia reperfusion injury, cholesterol-induced atherosclerosis, asbestos or silica-induced lung diseases, and MSU-induced gout.