Reference - Detail
| RRC ID | 11866 |
|---|---|
| Author | Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, Kisielow J, Hersberger M, Yamamoto M, Bachmann MF, Kopf M. |
| Title | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| Journal | Eur J Immunol |
| Abstract |
Oxidative stress and inflammation--two components of the natural host response to injury--constitute important etiologic factors in atherogenesis. The pro-inflammatory cytokine interleukin (IL)-1 significantly enhances atherosclerosis, however, the molecular mechanisms of IL-1 induction within the artery wall remain poorly understood. Here we have identified the oxidative stress-responsive transcription factor NF-E2-related 2 (Nrf2) as an essential positive regulator of inflammasome activation and IL-1-mediated vascular inflammation. We show that cholesterol crystals, which accumulate in atherosclerotic plaques, represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome. The resulting vigorous IL-1 response critically depended on expression of Nrf2, and Nrf2-deficient apolipoprotein E (Apoe)-/- mice were highly protected against diet-induced atherogenesis. Importantly, therapeutic neutralization of IL-1α and IL-1β reduced atherosclerosis in Nrf2+/- Apoe-/- but not in Nrf2-/- Apoe-/- mice, suggesting that the pro-atherogenic effect of Nrf2-signaling was primarily mediated by its permissive role in IL-1 production. Our studies demonstrate a role for Nrf2 in inflammasome activation, and identify cholesterol crystals as disease-relevant triggers of the NLRP3 inflammasome and potent pro-atherogenic cytokine responses. These findings suggest a common pathway through which oxidative stress and metabolic danger signals converge and mutually perpetuate the chronic vascular inflammation that drives atherosclerosis. |
| Volume | 41(7) |
| Pages | 2040-51 |
| Published | 2011-7-1 |
| DOI | 10.1002/eji.201041316 |
| PMID | 21484785 |
| MeSH | Animals Apolipoproteins E / deficiency Apolipoproteins E / genetics Apolipoproteins E / metabolism Atherosclerosis / metabolism* Atherosclerosis / pathology* Carrier Proteins / metabolism Caspase 1 / metabolism Cells, Cultured Cholesterol / chemistry Cholesterol / metabolism* Crystallization Dendritic Cells / metabolism Foam Cells / metabolism Inflammasomes / metabolism* Interleukin-1 / biosynthesis Interleukin-1 / metabolism* Macrophages / metabolism Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* NLR Family, Pyrin Domain-Containing 3 Protein Oxidative Stress Plaque, Atherosclerotic / metabolism Signal Transduction |
| IF | 4.404 |
| Times Cited | 165 |
| WOS Category | IMMUNOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| Total number of mentions | 0 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC01390 |