Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 10, Pages 3634-3646Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005663
Keywords
apolipoprotein; amyloid; atherosclerosis; cytokine induction; inflammation; interleukin; macrophage; oxidation-reduction (redox); Toll-like receptor (TLR); methionine oxidation; apolipoprotein A-I; cytokines; DAMP; inflammation; methionine oxidation
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Funding
- National Institutes of Health [R01 HL113059]
- Japan Society for the Promotion of Science's Invitation Fellowship Program for Research in Japan [L-14559]
- Associazione Italiana per la Ricerca sul Cancro [IG 2016-15434]
- Fondazione Telethon [GGP14144]
- Italian Ministry of Health Young Investigators Grant [GR-2016-02363630]
- MEXT-Supported Program for the Strategic Research Foundation at Private Universities [S1201007]
- MEXT Japan [24614018, 26461370, 15H02903]
- Grants-in-Aid for Scientific Research [24614018, 26461370] Funding Source: KAKEN
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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)-1 and secretion of the pro-inflammatory cytokines tumor necrosis factor (TNF) and IL-6 in mouse bone marrow-derived macrophages (BMDMs) and human primary monocytes. Additionally, secretion of mature IL-1 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.
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