Table 1.
Summary of nuclear receptors and their ligands involved in the NLRP3 inflammasome regulation (arranged in alphabetical order).
| NR | Mechanism | Effect | Cell type | Possible therapeutic | Used ligand | References |
|---|---|---|---|---|---|---|
| FXR (NR1H4) | Interacts with NLRP3 inflammasome components and prevents their assembly, in ligand dependent manner | ↓ NLRP3 inflammasome | Peritoneal macrophage, Raw246.7 Sepsis-associated cholestasis mouse model, FXR KO, FXR overexpression in THP-1 |
Protects mice from septic shock under cholestasis condition | GW-4064, DCA, CDCA, OCA | (81) |
| FXR (NR1H4) | Inhibits ER stress, attenuation of CHOP-dependent NLRP3 overexpression and inhibition of PERK activation | ↓ NLRP3 inflammasome | Mouse primary hepatocytes, AML12 cell line, FXR KO mouse | Inhibits ER stress, ameliorates hepatocyte death and liver injury | GW4064, chenodeoxycholic acid (CDCA) | (82) |
| FXR (NR1H4) | Inhibits oligomerization and ubiquitination of ASC | ↓ NLRP3 inflammasome | BMDM, peritoneal macrophages, PBMCs (FXR KO mice) | Ameliorates partially the symptoms of NLRP3-related disease models | GW4064, INT747 | (83) |
| LXR (NR1H) | Induces the expression of IL-1β, caspase-1, and NLRP3; Metabolic rewiring through Acetyl-CoA accumulation | ↑ NLRP3 inflammasome | Human monocytes | Induction of trained innate immunity | GW3965, T1317 (agonist), GSK2033 antagonist) | (84) |
| LXRβ (NR1H2) | Activates P2X7 receptor (non-genomic activity) | ↑ NLRP3 inflammasome | Colon cancer cell lines | As a target for Caspase-1 induced pyroptosis | T0901317 (agonist), LXRβ siRNA | (85) |
| PXR (NR1I2) | Enhances the expression of NLRP3 through binding to its promoter region | ↑ NLRP3 inflammasome | HUVECs, HepG2 | Protects against xenobiotic agents | Rifampicin, SR12813 (agonists) sulforaphane (antagonist) | (86) |
| PXR | Triggers release of ATP through pannexin-1 channels, P2X7 activation | ↑ NLRP3 inflammasome | Human macrophages (THP-1), Mouse Peritoneal macrophages, Nlrp3 KO and PXR KO mice | Link xenobiotic exposure to the innate immunity as potential conserved mechanism | Rifaximin and SR12813 (for human); 16a-carbonitrile (PCN) (for mouse) | (87) |
| PXR (NR1I2) | Blocks NF-κB binding to the promoter of NLRP3 | ↓ NLRP3 inflammasome | HUVECs | Statin via FXR act as an anti-inflammatory agent | Rifampicin, SR12813, mevastatin, simvastatin | (88) |
| PPARα (PPARA, NR1C1) | Knock out of PPARα associated with up regulation in the inflammasome components and hyper activation of NF-κB pathway | ↓ NLRP3 inflammasome | In vivo, PPARα KO mice subjected to P. aeruginosa, lung tissue | Protects lung tissue upon lung bacterial infection | Not used | (89) |
| PPARγ (PPARG, NR1C3) | Downregulates the expression inflammasome components | ↓ NLRP3 inflammasome | Radiation-induced acute intestinal injury rat model, peritoneal macrophage | Reduces radiation-induced intestinal inflammation | Rosiglitazone | (90) |
| PPARγ (PPARG, NR1C3) | Upregulates IFN-β which required for suppression of NLRP3-mediated IL-1β | PPARγ KO mice exhibit downregulation of NLRP3 inflammasome activation | PPARγ KO mice, Peritoneal macrophages, in vivo peritoneal cytokine assessment | Anti-inflammatory | T0070907 (antagonist) Rosiglitazone | (91) |
| PPARγ (PPARG, NR1C3) | Inhibition of IL-1β, caspase-1 and NLRP3 expression | ↓ NLRP3 inflammasome | In vivo, spinal cord injury (rat). Isolated Neurons from the spinal cord after spinal cord injury (SCI) | Anti-inflammatory protective effects in spinal cord injury | Rosiglitazone, G3335 (antagonist) | (92, 93) |
| PPARγ (PPARG, NR1C3) | Direct binding of PPARγ to NLRP3, inhibits its assembly | ↓ NLRP3 inflammasome | Peritoneal macrophages, PPARGC/− mice, (HEK293T cells/system), PBMCs | Regulate metabolic DAMPs- induced NLRP3 inflammasome | Rosiglitazone | (94) |
| PPARδ (PPARD, NR1C2) | Modulation of AMPK activity and ROS production, downregulates IL-1β, caspase-1 and NLRP3, NLRP6, NLRP10 | ↓ NLRP3 inflammasome | NAFLD mouse model, HepG2 | Ameliorates non-alcoholic fatty liver disease associated inflammation | GW501516 | (95) |
| PPARß/δ (PPARD, NR1C2) | Downregulation the expression of NLRP3 inflammasome components | ↓ NLRP3 inflammasome | MPTP mouse model of PD | Suppress NLRP3-mediated neuroinflammation in PD mouse model | GW501516 | (96) |
| RAR (RAR) | Enhances LPS -induced priming signal and glycolytic activity | ↑ NLRP3 inflammasome | Human macrophage- derived monocyte | Enhances inflammatory responses | ATRA | (97) |
| RAR (RAR) | Reduced level of ROS and endotoxins in circulation | ↓ NLRP3 inflammasome | Rat, in vivo study, total blood | Ameliorates alcohol toxicity in the brain | ATRA | (98) |
| RAR, RXR (RAR) (RXR) | Enhances flagellin-induced NF-κB/AP-1 activity, and TLR co-receptor CD14 | ↑ IL-1β Release | THP-1 (human monocyte) | Enhances flagellin-induced proinflammatory responses | ATRA, BMS753 (RARα agonist), LG100268 (RXRα agonist) | (99) |
| REV-ERBα (NR1D1) | Suppress NLRP3 transcription by binding to its promoter, and inhibit NF-κB signaling | ↓ NLRP3 inflammasome | REV-ERBα KO mice Peritoneal macrophage, RAW264.7, DSS-induced colitis mouse model |
Suppress experimental colitis | SR9009, hemin, GSK4112 | (100) |
| REV-ERBα (NR1D1) | Repress NLRP3 and IL-1β transcription by binding to its promoter | ↓ NLRP3 inflammasome | REV-ERBα KO mice RAW264.7, human macrophage, peritonitis and LPS/D-Galactosamine-induced fulminant hepatitis mice models |
Suppress experimental peritonitis and fulminant hepatitis | SR9009, hemin, SR10067 (REV-ERBα/β agonist) | (101) |
| RORγ (RORC, NR1F3) | Response elements for RORγ in the promoters of the Nlrp3 and Il1b genes | RORγ KO mice exhibit downregulation of NLRP3 inflammasome | BMDMs (RORγ KO mice), human primary macrophages, RAW267 | Anti-inflammatory | SR2211, SR1555 (inverse agonist) | (102) |
| SHP (NR0B2) | Inhibits interaction between NLRP3 and ASC | ↓ NLRP3 inflammasome | BMDM, SHP KO mice, HEK293T, THP-1 | Anti-inflammatory, protect against excessive pathologic responses, preserve the mitochondrial homeostasis | Fenofibrate, AICAR | (103) |
| VDR (VDR, NR1I1) | Attenuates hyperosmotic stress-induced oxidative stress through activation NRF2-antioxidant axis | ↓ NLRP3 inflammasome | Immortalized primary human corneal epithelial cell | Potential therapeutic agent to treat dry eye problems | Calcitriol (1,25-D) | (104) |
| VDR (VDR, NR1I1) | Suppress NF-κB nuclear translocation through binding to importin 4 | ↓ NLRP3 inflammasome | MRL/lpr mice, Mouse renal tubular epithelial cells | Potential therapeutic agent for lupus nephritis | Paricalcitol (agonist) | (105) |
| VDR (VDR, NR1I1) | Inhibits NLRB3 binding to NEK7, NLRP3-mediated (ASC) oligomerization, and (ROS) accumulation | ↓ NLRP3 inflammasome | Peritoneal macrophages, DSS-induced ulcerative colitis mouse model | Attenuates DSS-induced acute colitis in mice, inhibits CD4+ T cells generation and polarization Decrease M1/M2 macrophages ratio | Calcitriol (1,25-D) | (106) |
| VDR (VDR, NR1I1) | Enhances IL-1β secretion mediated by NLRP3 inflammasome | ↑ NLRP3 inflammasome | PMA-differentiated THP-1 | Enhances inflammatory response | 1,25(OH)2D3, 25(OH)D3, 7DHC, vitamin D3 | (107) |
| VDR (VDR, NR1I1) | Direct interaction with NLRP3, Inhibits BRCC3-mediates NLRP3 deubiquitylation | ↓ NLRP3 inflammasome | BMDMs, mouse peritoneal macrophages (Vdr KO mice) | Anti-inflammatory, increases the survival rate in murine models of sepsis | 1,25-D | (108) |
| VDR (VDR, NR1I1) | Modulates AhR/NF-κB signaling, downregulate inflammasome components | ↓ NLRP3 inflammasome | Periodontitis mouse model, gingival epithelium | Alleviates the periodontitis | 1,25-D | (109) |
If it is not stated as other, then listed ligands are agonists.