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

Journal article

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: Freigang, S; Ampenberger, F; Spohn, G; Heer, S; Shamshiev, A

• Publication status: Published
• Journal: European journal of immunology
• Volume: 41
• Issue: 7
• Pages: 2040-2051
• Publication date: 2011-07-01
• DOI: 10.1002/eji.201190044
• EISSN: 1521-4141
• ISSN: 0014-2980
• Language: English
• Keywords: Carrier Proteins; Inflammasomes; Dendritic Cells; Interleukin-1; Cholesterol; Macrophages; Caspase 1; NF-E2-Related Factor 2; Crystallization; Animals; Cells, Cultured; Signal Transduction; Mice, Knockout; Mice, Inbred C57BL; Apolipoproteins E; Foam Cells; Mice; Plaque, Atherosclerotic; Atherosclerosis; Oxidative Stress