| RRC ID |
11866
|
| 著者 |
Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, Kisielow J, Hersberger M, Yamamoto M, Bachmann MF, Kopf M.
|
| タイトル |
Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.
|
| ジャーナル |
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.
|
| 巻・号 |
41(7)
|
| ページ |
2040-51
|
| 公開日 |
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
|
| 引用数 |
165
|
|
WOS 分野
|
IMMUNOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC01390 |
