Atherogenic oxoaldehyde of cholesterol induces innate immune response in monocytes and macrophages

Cell Biochem Biophys. 2021 Sep;79(3):649-658. doi: 10.1007/s12013-021-01004-w. Epub 2021 Jun 15.

Abstract

Cholesterol oxidation product, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (cholesterol 5,6-secosterol, ChSeco or Atheronal-A), formed at inflammatory sites, has been shown to promote monocyte differentiation into macrophages and cause elevated expression of macrophage scavenger receptors. Since inflammation is a key event at all stages of atherosclerotic plaque formation, the pro-inflammatory actions of ChSeco in human THP-1 monocytes and mouse J774 macrophages were investigated in the present study by employing ELISA, qRT-PCR, and functional assays. An increase in the secretion of interleukin-8 and platelet-derived growth factor (PDGF) isoform AA and, to a limited extent, PDGF isoform BB was observed into the culture medium of THP-1 monocytes exposed to ChSeco. However, no changes were seen in the secretion of tumor necrosis factor-alpha. In J774 macrophages treated with ChSeco, there was an upregulation of gene expression of several pro-inflammatory cytokines and their receptors. Concomitantly, there was down-regulation of gene expression of interleukin-1ß, interleukin-10, and lymphotoxin-beta. An increase in the release of interleukin-18 and chemokine (C-C motif) ligand-20 from J774 macrophages (which corroborated well with their gene expression profiles) and increased binding of THP-1 monocytes to ChSeco-exposed human aortic endothelial cells were observed. The results of the present study, for the first time, demonstrate the pro-inflammatory action of ChSeco and suggest the underlying pro-atherogenic mechanisms. These could be mediated through enhanced monocyte recruitment into the sub-endothelial space and subsequent proliferation of smooth muscle cells under the influence of monocyte-derived PDGF.

Keywords: Atherogenesis; Atheronals A and B; Cholesterol secoaldehyde; Gene and protein expression; Ozone; Pro-inflammatory cytokines and receptors; Singlet oxygen.

MeSH terms

  • Aldehydes / pharmacology
  • Animals
  • Atherosclerosis* / immunology
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Cell Line
  • Cholesterol* / metabolism
  • Cytokines / metabolism
  • Humans
  • Immunity, Innate* / drug effects
  • Macrophages* / cytology
  • Macrophages* / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Monocytes* / cytology
  • Monocytes* / drug effects
  • Monocytes* / metabolism
  • Platelet-Derived Growth Factor / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • THP-1 Cells

Substances

  • Cholesterol
  • Cytokines
  • Aldehydes
  • Platelet-Derived Growth Factor