Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule

Andrzej Witkowski, Sonia Carta, Rui Lu, Shinji Yokoyama, Anna Rubartelli, Giorgio Cavigiolio

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Amyloid deposits of apolipoprotein A-I (apoA-I) and inflammation are common in atherosclerotic arteries. In this study, we investigated the interplay between oxidation of apoA-I methionine residues (Met(O)-ApoA-I), a known amyloidogenic modification of apoA-I, and the inflammatory response of immune cells. Soluble pre-fibrillar Met(O)-ApoA-I, but not apoA-I, induced intracellular accumulation of pro-interleukin (IL)-1β and secretion of the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and IL-6 in mouse bone marrow-derived macrophages (BMDMs) and human primary monocytes. Additionally, secretion of mature IL-1β was also activated in human monocytes. The pro-inflammatory activity of Met(O)-ApoA-I was Toll-like receptor 4 (TLR4)-dependent and CD36-independent and was solely determined by oxidation of apoA-I methionine residues, in particular Met-86 and Met-148. In contrast, amyloid fibrils or reconstituted high-density lipoproteins (HDLs) generated from Met(O)-ApoA-I did not induce cytokine production in BMDMs. Although lipid-free Met(O)-ApoA-I remained functional in extracting lipids from cells and generating HDL, it gained strong pro-inflammatory properties that may aggravate local inflammation in the arteries and atherosclerosis. Our study indicates that oxidation of apoA-I methionine residues produces a potent danger-associated molecular pattern capable of stimulating pro-inflammatory cytokine secretion at levels similar to those induced by known pathogen-associated molecular patterns, such as lipopolysaccharide.

Original languageEnglish
Pages (from-to)3634-3646
Number of pages13
JournalThe Journal of biological chemistry
Issue number10
Publication statusPublished - Mar 8 2019


  • amyloid
  • apolipoprotein
  • apolipoprotein A-I
  • atherosclerosis
  • cytokine induction
  • cytokines
  • DAMP
  • inflammation
  • interleukin
  • macrophage
  • methionine oxidation
  • oxidation-reduction (redox)
  • Toll-like receptor (TLR)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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