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. 2011 Jul;41(7):2040-51.
doi: 10.1002/eji.201041316. Epub 2011 Jun 8.

Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis

Stefan Freigang  1 , Franziska Ampenberger, Gunther Spohn, Sebastian Heer, Abdijapar T Shamshiev, Jan Kisielow, Martin Hersberger, Masayuki Yamamoto, Martin F Bachmann, Manfred Kopf
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Free article

Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis

Stefan Freigang et al. Eur J Immunol. 2011 Jul.
Free article

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.

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