Table 1.
The role of Nrf2 in major inflammatory diseases (animal studies).
| Disease | Animal Model | Nrf2 Gain-of Function (Including Nrf2 Agonist) or Loss-of-Function |
Phenotype | Refs. |
|---|---|---|---|---|
| Obesity | C57BL/6J mice WT and Nrf2-disrupted; high fat diet (HFD) | Nrf2 loss-of-function, Nrf2 agonist (CDDO-Im) |
Improvement of obesity and suppression of lipogenesis by CDDO-Im. This beneficial is lost in Nrf2-deficient mice | [112] |
| C57BL/6J mice WT and Keap1-hypo; HFD | Nrf2 gain-of function (Hypomorphic Keap1 allele) |
Hypomorphic Keap1 allele mice (model of Nrf2 activation) gain less weight, show ameliorated glucose tolerance, and develop less hepatic steatosis. Keap1-hypo livers exhibit activated AMPK signaling | [113] | |
| C57BL/6J mice; HFD | Nrf2 agonist (Otipraz) | Administration of Nrf2 activator reverses the detrimental effects of HFD-induced obesity. | [114] | |
| C57BL/6J ob/ob mice | Nrf2 loss-of-function (Global and adipocyte-specific) |
Global, as well as adipose-specific, ablation of Nrf2 in ob/ob mice results in severe metabolic syndrome | [115] | |
| C57BL/6J HFD | Nrf2 loss-of-function (Adipocyte-specific Nrf2−/−) |
Adipocyte-specific Nrf2−/− impaires glucose tolerance, higher fasting glucose levels, and higher levels of cholesterol and non-esterified fatty acids. | [116] | |
| ob/ob mice | Nrf2 gain-of function (Keap1−/−) | Reduces epididymal fat mass and body weight | [121] | |
| Inflammatory Bowel Disease | salmonella typhimurium challenge model, dextran sodium sulfate (DSS)-induced colitis model | Nrf2 gain-of function by prohibitin B overexpression (transgenic mice) | Prohibitin B transenic mice exhibit decreases oxidative stress and improved colitis | [144] |
| DSS-induced colitis | Nrf2 loss-of-function (Mitogen-activated protein kinase phosphatase 1 KO; Mkp-1−/−) |
Mkp-1−/− mice are more susceptible to DSS-induced colitis | [145] | |
| DSS-induced colitis | Nrf2-deficient mice | Increased inflammation and mucosal damage | [146] | |
| DSS-induced colitis | Dehydroepiandrosterone (DHEA); acivates Nrf2 via G protein-coupled receptor 30 (GPR30)-dependent pathway | DHEA inhibits intestinal inflammation and improves barrier function in DSS-induced colitis model | [149] | |
| DSS-induced colitis | Nrf2 inhibition by treating HO-1 inhibitor zinc protoporphyrin IX (ZnPP) | Administration of ZnPP blunts the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206 | [151] | |
| DSS-induced colitis | Nrf2 activation by CDDO-Im | Administration of CDDO-Im improves the altered colonic histology, and cytokine | [153] | |
| DSS-induced colitis | Nrf2 activation by GB1a | GB1a administration reverses loss of body weight and disease activity index scores in experimental colitis | [154] | |
| DSS-induced colitis | Nrf2 activation by dimethyl fumarate (DMF) | DMF attenuates the shortening of colons and alleviated colonic inflammation | [51,154,155] | |
| DSS-induced colitis | Nrf2 activation by Maresin 1 and Nrf2 inhibition by ML385 | Maresin 1 attenuates experimental colitis by reducing activation of TLR4/NF-κB. ML385 reverses the protective effects of maresin 1 markedly | [157] | |
| 4,6-trinitro-benzenesulfonic acid (TNBS) induced colitis | Nrf2 activation by Imperatorin | Imperatorin administration alleviates the symptoms of ulcerative colitis and inhibited the secretion of TNF-α and IL-6 | [160] | |
| Acetic acid (AA)-induced colitis in rats | Nrf2 activation by Olmerartan | Olmerartan ameliorates colon injury and inflammatory signs | [161] | |
| Systemic Lupus Erythematosus | Female Nrf2−/− mice | Nrf2-deficient mice | Multiorgan inflammatory lesions Apearance of anti-double-stranded DNA antibodies in young adulthoodintravascular Pemature death due to rapidly progressing membranoproliferative glomerular nephritis |
[167] |
| B6/lpr mouse (sponatenous lupus nephritis model) | Nrf2-deficient mice | Nrf2 deficiency increases lupus nephritis and Th17 cell numners in B6/lpr mice | [66] | |
| MRL/lpr mouse | Nrf2-deficient mice | Nrf2 deficiency increases life span, improves nephritis. Immunologic abnormalities as well as hypergammaglobulinemia is correctetd. | [168] | |
| NZB/W mouse (spontaneous lupus nephritis model) | Nrf2 activation by A-1396076 | A-1396076 dampens inflammation in an IFN-α-accelerated NZB/W mouse lupus nephritis model | [171] | |
| B6.Sle1.Sle3 mouse and MRL/lpr mouse | Nrf2 activation by CDDO-Me | CDDO-Me reduces severity of lupus disease by attenuating MEK-1/2, ERK, and STAT-3 signaling in CD4+ T cells, as well as oxidative stress in B6.Sle1.Sle3 mice or MRL/lpr mice | [172] | |
| Pristane-induced lupus nephritis mice | Nrf2 activation by DMF | DMF ameliorates pristane-induced lupus nephritis mice, and showes stronger anti-inflammatory and organ-protective effects than glucocorticoids | [173] | |
| Pristane-induced lupus nephritis mice | Nrf2 activation by sulphoraphane | Sulphoraphane suppresses pritane-induced lupus nephritis | [174] | |
| Rheumatoid Arthritis | Complete Freund’s adjuvant-induced arthritis in rats | Nrf2 activation by DMF | DMF ameliorates complete Freund’s adjuvant-induced arthritis by suppressing oxidative stress and inflammatory mediators, and by increasing local Nrf2 and HO-1 concentration in the involved joints | [178] |
| Collagen-induced arthritis in DBA/1 mice | Nrf2 activation by kurarinone | Kurarinone reduces arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines in the serum and paw tissues | [182] | |
| Collagen-induced arthritis in DBA/1 mice | Nrf2 activation by oleuropein | Oleuropein containing diet prevents histological damage and arthritic score development | [183] | |
| Collagen-induced arthritis in DBA/1 mice | NR1D1 activation by SR9009 increases Nrf2-associated enzymes. | SR9009 significantly suppresses synovial hyperplasia, infiltration of inflammatory cells, and destruction of cartilage and bone in mice with CIA | [184]. | |
| Collagen-induced arthritis in DBA/1 mice | Nrf2 activation by DC32, a dihydroartemisinin derivative | DC32 significantly alleviates footpad inflammation, reduce cartilage degradation | [185] |