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

Research output: Contribution to journalArticle

Abstract

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
Volume294
Issue number10
DOIs
Publication statusPublished - Mar 8 2019

Fingerprint

Apolipoprotein A-I
Methionine
Oxidation
Molecules
Macrophages
HDL Lipoproteins
Cytokines
Interleukin-1
Amyloid
Monocytes
Bone
human APOA1 protein
Arteries
Inflammation
Lipids
Toll-Like Receptor 4
Amyloid Plaques
Lipopolysaccharides
Interleukin-6
Atherosclerosis

Keywords

  • 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

Cite this

Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule. / Witkowski, Andrzej; Carta, Sonia; Lu, Rui; Yokoyama, Shinji; Rubartelli, Anna; Cavigiolio, Giorgio.

In: The Journal of biological chemistry, Vol. 294, No. 10, 08.03.2019, p. 3634-3646.

Research output: Contribution to journalArticle

Witkowski, Andrzej ; Carta, Sonia ; Lu, Rui ; Yokoyama, Shinji ; Rubartelli, Anna ; Cavigiolio, Giorgio. / Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule. In: The Journal of biological chemistry. 2019 ; Vol. 294, No. 10. pp. 3634-3646.
@article{a578c242472443b5ae7405e0c14460e9,
title = "Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule",
abstract = "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.",
keywords = "amyloid, apolipoprotein, apolipoprotein A-I, atherosclerosis, cytokine induction, cytokines, DAMP, inflammation, interleukin, macrophage, methionine oxidation, oxidation-reduction (redox), Toll-like receptor (TLR)",
author = "Andrzej Witkowski and Sonia Carta and Rui Lu and Shinji Yokoyama and Anna Rubartelli and Giorgio Cavigiolio",
year = "2019",
month = "3",
day = "8",
doi = "10.1074/jbc.RA118.005663",
language = "English",
volume = "294",
pages = "3634--3646",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule

AU - Witkowski, Andrzej

AU - Carta, Sonia

AU - Lu, Rui

AU - Yokoyama, Shinji

AU - Rubartelli, Anna

AU - Cavigiolio, Giorgio

PY - 2019/3/8

Y1 - 2019/3/8

N2 - 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.

AB - 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.

KW - amyloid

KW - apolipoprotein

KW - apolipoprotein A-I

KW - atherosclerosis

KW - cytokine induction

KW - cytokines

KW - DAMP

KW - inflammation

KW - interleukin

KW - macrophage

KW - methionine oxidation

KW - oxidation-reduction (redox)

KW - Toll-like receptor (TLR)

UR - http://www.scopus.com/inward/record.url?scp=85062631526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062631526&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.005663

DO - 10.1074/jbc.RA118.005663

M3 - Article

C2 - 30635405

AN - SCOPUS:85062631526

VL - 294

SP - 3634

EP - 3646

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 10

ER -