Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

Abstract

The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.

Keywords: NLRP3; circadian rhythm; inflammasome; inflammation and innate immunity; inflammatory disease; nuclear receptors; therapeutic strategy.

Figure 1

Regulatory activities of nuclear receptors on the NLRP3 inflammasome priming and activation steps. The priming (first step) of the NLRP3 inflammasome requires the binding and activation of PRRs (TLRs,…) by PAMPs such as LPS, cytokines or ox-LDL, resulting in the transcription of the NLRP3 inflammasome components. Its activation (second step) is the result of recognition of PAMPs (such as the bacterial pore-forming toxin nigericin) or DAMPs which are released by damaged or dying cells (such as ATP) following injury or metabolic imbalance (such as mtROS), or accumulate in tissues (such as crystals). These lead to lysosomal damage, mitochondrial damages (exposition of cardiolipin, mtDNA) which ultimately modify ion (K⁺, Ca²⁺) fluxes. Upon this two-step process, the NLRP3 inflammasome assembles, caspase 1 is activated, Gasdermin-D and pro-IL-1β and pro-IL-18 are cleaved, leading to mature cytokines secretion and cell death by pyroptosis. The activity of nuclear receptors on each step is indicated when appropriate. ASC, apoptosis-associated speck-like protein containing a CARD domain; ATP, adenosine triphosphate; BRCC3, Lys-63-specific deubiquitinase BRCC36; casp, caspase; CLIC, chloride intracellular channels; DAMPs, damage-associated molecular patterns; GSDMD, gasdermin-D; IL, interleukin; IL1R, interleukin-1 receptor; LPS, lipopolysaccharide; MAM, Mitochondria-associated ER membranes; mtoxDNA, mitochondrial oxidized DNA; NFκB, nuclear factor-kappa B; NLRP3, nucleotide-binding, LRR and PYD domains-containing protein 3; Ox-LDL, oxidized low-density lipoproteins; P, Phosphate; PAMPs, pathogen-associated molecular patterns; Panx1, Pannexin-1; PRRs, Pattern Recognition Receptors; ROS, reactive oxygen species; P2X7, purinergic receptor P2X7; TLR, Toll-like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TWIK2, two-pore domain weak inwardly rectifying K⁺ channel; TXNIP, Thioredoxin-interacting protein Ub, ubiquitin. (+): activates; (−): inhibits.

Figure 2

Structure and function of nuclear receptors. (A) Canonical structures of nuclear receptors. Nuclear receptors are composed of a N terminal activation function domain whose activity is independent of ligand binding, a DNA binding domain (DBD), a hinge region (Hr) and a ligand binding domain (LBD). Their respective activity is mentioned accordingly. Dimer: dimerization (B) Nuclear receptors work as homo or heterodimers which bind a response element present in the promoter of their target genes. Response elements are composed of two AGGTCA half-sites separated by one to four nucleotides (X). In the absence of ligand, NRs (except class I) preferentially bind co-repressor and inhibit gene transcription. In the presence of a ligand, co-repressors are degraded by the proteasome and co-activators are recruited, which then allows the binding of a mediator complex and the ARN polymerase II.