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)-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. Conditions such as atherosclerosis, Alzheimer's disease, and type 2 diabetes are often described as sterile inflammation dis

High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction

“…However, while research in atherosclerotic disease has indicated that the oxidation of methionine residues in human apoA-I can serve as a potent inflammasome activator [172], no clinical studies have definitively established a direct link between oxidized HDL components and the activation of the NLRP3 inflammasome signaling pathway during MI. Therefore, it is imperative to conduct further investigations to explore the specific pro-inflammatory mechanisms arising from oxidized HDL components.…”

Advanced and Innovative Nano-Systems for Anticancer Targeted Drug Delivery

“…Scavenger receptor class B type I (SR-BI) is overexpressed in tumor cells and participates in the cholesterol metabolism of tumor cells [ 74 , 75 ]. ApoA-I can specifically target SR-BI and mediate the anti-inflammatory ability of macrophages by regulating the production of cytokines in macrophages [ 76 ]. Therefore, SR-BI can be used as a specific target for the treatment of common tumors such as breast cancer, ovarian cancer and prostate cancer [ 77 , 78 ] ( Figure 3 B).…”

Unraveling the Complexity of HDL Remodeling: On the Hunt to Restore HDL Quality

“…While Met(O)-ApoA-I monomers increase CEC, they also initiate amyloidogenesis which ultimately results in the sequestration and inactivation of otherwise antiatherogenic and HDL-forming ApoA-I [54]. Met86(O)-ApoA-I and Met148(O)-ApoA-I have been reported to maintain their cholesterol-accepting capacity while strongly inducing pro-inflammatory cytokine production in surrounding immune cells [55], contributing to atherosclerotic disease progression. MPO overexpression in atherosclerotic lesions is also known to result in chlorination and nitration of ApoA-I tyrosine residues.…”