Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.
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 a...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2011
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| _version_ | 1797104040242315264 |
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| author | Freigang, S Ampenberger, F Spohn, G Heer, S Shamshiev, A Kisielow, J Hersberger, M Yamamoto, M Bachmann, M Kopf, M |
| author_facet | Freigang, S Ampenberger, F Spohn, G Heer, S Shamshiev, A Kisielow, J Hersberger, M Yamamoto, M Bachmann, M Kopf, M |
| author_sort | Freigang, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:28:15Z |
| format | Journal article |
| id | oxford-uuid:f510e926-c452-462c-8cd7-c7888255f6eb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:28:15Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:f510e926-c452-462c-8cd7-c7888255f6eb2022-03-27T12:24:31ZNrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f510e926-c452-462c-8cd7-c7888255f6ebEnglishSymplectic Elements at Oxford2011Freigang, SAmpenberger, FSpohn, GHeer, SShamshiev, AKisielow, JHersberger, MYamamoto, MBachmann, MKopf, MOxidative 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. |
| spellingShingle | Freigang, S Ampenberger, F Spohn, G Heer, S Shamshiev, A Kisielow, J Hersberger, M Yamamoto, M Bachmann, M Kopf, M Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title_full | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title_fullStr | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title_full_unstemmed | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title_short | Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. |
| title_sort | nrf2 is essential for cholesterol crystal induced inflammasome activation and exacerbation of atherosclerosis |
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