title: Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.
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.
authors.affiliation: Molecular Biomedicine, Institute of Integrative Biology, ETH Zurich, Schlieren, Switzerland. stefan.freigang@env.ethz.ch
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
authors.forename: Franziska
authors.initials: F
authors.lastname: Ampenberger
authors.forename: Gunther
authors.initials: G
authors.lastname: Spohn
authors.forename: Sebastian
authors.initials: S
authors.lastname: Heer
authors.forename: Abdijapar T
authors.initials: AT
authors.lastname: Shamshiev
authors.forename: Jan
authors.initials: J
authors.lastname: Kisielow
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D003460:Crystallization; D003713:Dendritic Cells / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; D002784:Cholesterol; D020170:Caspase 1