Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages

Anne Marie Kuhn, Nico Tzieply, Martina Victoria Schmidt, Andreas Von Knethen, Dmitry Namgaladze, Masayuki Yamamoto, Bernhard Brüne

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Inflammatory conditions and oxidative stress contribute to the development of atherosclerosis. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective properties. Its role in effecting a deactivated state of oxidized low-density lipoprotein (oxLDL)-generated foam cell macrophages (FCMs), a prevailing cellular phenotype of atherosclerotic lesions, has not been investigated yet. In this study RAW264.7- or mouse peritoneal macrophage-derived FCMs showed reduced mRNA expression of proinflammatory cytokines such as IL-1β and IL-6 and an attenuated production of reactive oxygen species (ROS), as analyzed by hydroethidine in response to lipopolysaccharide (LPS) and compared to LPS-treated control macrophages. In peritoneal FCMs from Nrf2-/- mice (C57BL/6J), the LPS-induced proinflammatory response was restored. OxLDL induced heme oxygenase (HO)-1, which was Nrf2-dependent, and inhibition of HO-1 activity in FCMs using zinc protoporphyrin-IX allowed the cells to regain a proinflammatory phenotype. Mechanistically, oxLDL attenuated ROS-dependent activation of CCAAT/enhancer binding protein (C/EBP) family members in FCMs, thereby reducing cytokine expression. Thus, in FCMs the Nrf2/HO-1 axis intervenes in LPS signaling. ROS production is impaired, C/EBP transactivation is reduced, and consequently the expression of proinflammatory mediators is attenuated, thereby shaping a desensitized FCM phenotype. This macrophage phenotype may be important for the progression of atherosclerosis.

Original languageEnglish
Pages (from-to)1382-1391
Number of pages10
JournalFree Radical Biology and Medicine
Volume50
Issue number10
DOIs
Publication statusPublished - 2011 May 15

Keywords

  • C/EBP
  • Desensitized phagocytes
  • Foam cell
  • Free radicals
  • Nrf2
  • OxLDL

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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