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

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

Research output: Contribution to journalArticle

167 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2040-2051
Number of pages12
JournalEuropean Journal of Immunology
Volume41
Issue number7
DOIs
Publication statusPublished - 2011 Jul

Keywords

  • Anti-oxidant response
  • Atherosclerosis
  • Inflammation
  • Interleukin-1
  • Nrf2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Freigang, S., Ampenberger, F., Spohn, G., Heer, S., Shamshiev, A. T., Kisielow, J., Hersberger, M., Yamamoto, M., Bachmann, M. F., & Kopf, M. (2011). Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. European Journal of Immunology, 41(7), 2040-2051. https://doi.org/10.1002/eji.201041316