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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.
Highlights
Amyloid deposits of apolipoprotein A-I and inflammation are common in atherosclerotic arteries
Our study indicates that oxidation of apolipoprotein A-I (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
Toll-like receptors (TLRs) are triggered by microbial components, sterile inflammation is mediated by endogenous molecules that work as signal 1 either in their native conformation or after redox-mediated changes [20] and that are released by injured cells and tissues (danger-associated molecular patterns (DAMPs))
Summary
1.6 Ϯ 0.0 29.7 Ϯ 0.0 85.7 Ϯ 0.7 99.0 Ϯ 0.1 abundant (24 –26, 28), suggesting an association between apoA-I amyloid formation and atherosclerosis. The plasma concentration of lipid-free apoA-I is very low, compared with that of HDL-associated apoA-I (36 –39), recent studies detected much higher levels of lipid-free apoA-I in the subendothelial space of the arteries, compared with plasma, and a 100-fold increase in atherosclerotic lesions, compared with normal arteries [40]. This lipid-free apoA-I is heavily oxidized [41,42,43] and crosslinked [40]. Further details of the molecular and cellular mechanisms underlying such response were investigated
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