Table 2.
Novel experimental agents targeting NLRs for autoimmune diseases treatment
| Disease | Targets | Agents | Experimental model | Outcomes | Potential mechanisms | References |
|---|---|---|---|---|---|---|
| IBD | NLRC2 | SB203580 | DSS-induced murine colitis | ↓Clinical score, ↓Inflammatory cytokines | Blocking activation of p38/MAPK and RIP2/NOD2/NF-κB signaling pathways | [105] |
| GSK583 | Intestinal mucosal tissue from IBD patients | ↓Inflammatory cytokines | Blocking activation of RIP2/NOD2 signaling pathway | [106] | ||
| NLRP3 | Wogonoside | THP-1 cell, DSS-induced murine colitis | ↓Inflammatory cells infiltration | Blocking activation of NF-κB and NLRP3 inflammasome | [111] | |
| Alpinetin | THP-1 cell, DSS-induced murine colitis | ↓Colonic pathological damage | Suppressing TLR4 and NLRP3 signaling pathways | [112] | ||
| Oroxylin A | THP-1 cell, BMDM, DSS-induced murine colitis | ↓Inflammatory cells infiltration | Suppressing ASC speck formation and NLRP3 inflammasome assembly, inhibiting NF-κB p65 expression and nuclear translocation | [113] | ||
| Naringin | RAW264.7 cell, DSS-induced murine colitis | ↓DAI, ↓colonic pathological damage | Blocking activation of NF-κB, MAPK and NLRP3 inflammasome | [114] | ||
| Asiatic acid | THP-1 cell, DSS-induced murine colitis | ↓DAI, ↓histopathologic scores | Suppressing mitochondria-mediated NLRP3 inflammasome activation | [115] | ||
| Dimethyl fumarate | THP-1 cell, BMDM, DSS-induced murine colitis | ↓Colonic pathological damage | Activating Nrf2 and suppressing NLRP3 inflammasome activation | [116] | ||
| miR-223 | BMDM, neutrophil, DSS-induced murine colitis | ↓Inflammatory cytokines | Controlling myeloid-specific NLRP3 inflammasome activity | [117] | ||
| MCC950 | Spontaneous chronic colitis mouse model Winnie | ↓DAI, ↓colonic pathological damage | Small-molecule inhibitor of NLRP3, blocking activation of NLRP3 inflammasome | [118] | ||
| NLRP1 | SDG | RAW264.7 cell, DSS-induced murine colitis | ↓Macrophage infiltration, ↓histopathologic scores | Blocking activation of NLRP1 inflammasome and NF-κB | [119] | |
| NLRP6 | Apigenin | DSS-induced murine colitis | ↓DAI, ↓colonic pathological damage | Modulating gut microbiota through regulating NLRP6 signaling pathway | [120] | |
| CIITA | Curcumin | Colonic epithelial cells | ↓Disease severity, ↓T cell chemokines | Suppressing transcription level of MHC-II and CIITA induced by IFN-γ | [149] | |
| NLRX1 | NX-13 | DSS-induced murine colitis | ↓Disease severity, ↓leukocytic infiltration | Activating NLRX1 to mediate a resistance to both NF-κB activity and oxidative phosphorylation | [151] | |
| RA | NLRC2 | 2E7 | Collagen-induced arthritis murine model, Collagen antibody-induced arthritis murine model | ↓Paw Swelling, ↓inflammatory cytokines | Targeting MDP and blocking NOD2-mediated pathways | [107] |
| NLRC5 | FER1L4 | CFA-induced adjuvant arthritis rat model | ↓Paw Swelling, ↓inflammatory cytokines | Targeting NLRC5 and decreasing expression of NLRC5 | [109] | |
| MEG3 | CFA-induced adjuvant arthritis rat model | ↓Paw Swelling, ↓inflammatory cytokines | Targeting NLRC5 and decreasing expression of NLRC5 | [110] | ||
| NLRP3 | Taraxasterol | IL-1β-stimulated human FLS, Collagen-induced arthritis murine model | ↓Paw Swelling, ↓inflammatory cytokines | Blocking activation of NF-κB and suppressing NLRP3 inflammasome through blocking expressions of NLRP3, ASC and caspase-1 | [121] | |
| Curculigoside A | CFA-induced adjuvant arthritis rat model | ↓Arthritis index, ↓inflammatory cytokines | Blocking activation of NF-κB and NLRP3 inflammasome | [122] | ||
| Methotrexate | Collagen-induced arthritis murine model | ↓Paw Swelling, ↓inflammatory cytokines | Blocking the activation of NF-κB and NLRP3/Caspase-1 pathways, regulating the inflammation related metabolic networks | [123] | ||
| SLE | NLRP3 | Icariin | MRL/lpr mice | ↓Renal tissue damage, ↓inflammatory cytokines | Blocking activation of NF-κB and NLRP3 inflammasome | [125] |
| Sophocarpine | MRL/lpr mice | ↓Urine protein, ↓renal tissue damage | Blocking activation of NF-κB and NLRP3 inflammasome | [126] | ||
| Piperine | HK-2 cell, Pristane-induced SLE murine model | ↓Inflammatory cytokines | Blocking AMPK-mediated activation of NLRP3 inflammasome | [127] | ||
| Curcumin | MRL/lpr mice | ↓Urine protein, ↓renal tissue damage | Blocking activation of NLRP3 inflammasome | [128] | ||
| Procyanidin B2 | MRL/lpr mice | ↓Urine protein, ↓renal tissue damage | Inhibiting the activation of NLRP3 inflammasome and the production of cytokines | [129] | ||
| Melatonin | Pristane-induced SLE murine model | ↓Renal tissue damage | Enhancing the Nrf2 activation and inhibiting NLRP3 inflammasome activation | [130] | ||
| Baicalein | MDSC, Pristane-induced murine model | ↓Urine protein, ↓renal tissue damage | Regulating the balance of the Nrf2/HO-1 signal and NLRP3 expression | [131] | ||
| M1 | MDSC, J774A.1 cell, LPS-induced murine ASLN model | ↓Urine protein, ↓renal tissue damage | Activating the sirtuin3/autophagy axis and inhibiting NLRP3 inflammasome activation | [133] | ||
| Let-7f-5p | SLE patients, MRL/lpr mice | ↓Inflammatory cytokines | Directly targeting NLRP3 and inhibiting NLRP3 expression | [134] | ||
| Psoriasis | NLRP3 | BAY 11-7082 | IMQ-induced psoriasis-like dermatitis murine model | ↓Epidermal thickness, ↓inflammatory cells infiltration | Blocking activation of NF-κB and NLRP3 inflammasome | [135] |
| Cycloastragenol | BMDM, IMQ-induced psoriasis-like dermatitis murine model | ↓epidermal thickness, ↓dermal infiltration of macrophages | Suppressing NLRP3 inflammasome complex assembly and NLRP3 inflammasome-mediated pyroptosis | [138] | ||
| Datura Metel L. | IMQ-induced psoriasis-like dermatitis murine model | ↓Inflammatory cytokines | Decreasing expression of IKKα, NF-κB, ASC, NLRP3 and caspase-1 | [137] | ||
| MS | NLRC2 | 2E7 | MOG35–55-induced EAE murine model | ↓Progress and ↓severity | Targeting MDP and blocking NOD2-mediated pathways | [107] |
| MIS416 | MOG35–55-induced EAE murine model | ↓Progress and ↓severity | Inhibiting inflammatory T-cell activity by activating TLR9 and NOD2 | [108] | ||
| NLRP3 | MCC950 | BMDM, MOG35–55-induced EAE murine model | ↓Clinical symptoms, ↓inflammatory cytokines | Small-molecule inhibitor of NLRP3, blocking activation of NLRP3 inflammasome | [139] | |
| JC-171 | BMDM, J774A.1 cell, MOG35–55-induced EAE murine model | ↓Progress and ↓severity | Small-molecule inhibitor of NLRP3 inflammasome, inhibiting NLRP3/ASC interaction and IL-1β production | [141] | ||
| OLT1177 | MOG35–55-induced EAE murine model | ↓Infiltration of CD4 T cells and macrophages | Selective inhibitor of NLRP3 inflammasome, inhibiting production of inflammatory cytokines | [142] | ||
| Prednisone | Cuprizone-induced demyelination murine model | ↓Progress and ↓severity | Blocking activation of NLRP3 inflammasome and production of related inflammatory cytokines | [143] | ||
| Tetramethylpyrazine | MOG35–55-induced EAE murine model | ↓Clinical scores and ↓demyelination | Reducing the expression of NLRP3 inflammasome and modulating the Th1/Th17/Th2 response | [144] | ||
| CIITA | Diarylpropionitrile | PLP-induced EAE murine model | ↓Progress and ↓severity | Abrogating CIITA expression and hampering IRF-1 to translocate into nucleus | [150] | |
| T1D | NLRP3 | LMP | Non-obese diabetic mice | ↓Progress and ↓fasting glucose levels | Upregulating claudin-1 and ZO-2 expression, blocking NLRP3 inflammasome activation, increasing Treg frequencies | [146] |
| Ginsenoside Rg1 | Streptozotocin-induced T1D murine model | ↓Fasting glucose levels, ↑insulin secretion | Blocking activation of NLRP3 and regulating Keap1/Nrf2/HO-1 pathways | [147] | ||
| AIH | NLRP3 | miR223 | Hepatic S100-induced AIH murine model | ↓Liver injury | Downregulating the expression of NLRP3 and caspase-1 | [148] |
IBD inflammatory bowel disease, SLE systemic lupus erythematosus, MS multiple sclerosis, RA rheumatoid arthritis, GA gout arthritis, T1D type 1 diabetes, AIH autoimmune hepatitis, BMDM bone marrow derived macrophage, MDSC myeloid-derived suppressor cell, EAE experimental autoimmune encephalomyelitis, DSS dextran sulfate sodium, LPS lipopolysaccharide, DAI disease activities index, ↑ up, ↓ down.