Oxidation of methionine residues in human apolipoprotein A-I generates a potent pro-inflammatory molecule
Year: 2019
Type: article
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.
Source: Journal of Biological Chemistry
Authors: Andrzej Witkowski, Sonia Carta, Rui Lu, Shinji Yokoyama, Anna Rubartelli, Giorgio Cavigiolio
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: Ministry of Education, Culture, Sports, Science and Technology, Fondazione Telethon, Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, University of California, San Francisco, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute
Awards: G1252650050, Impact of self-association on structure and function of apolipoprotein A-I, Agilent 6490 Triple Quadrupole Mass Spectrometer, G3219096868, G3253891822, G3371644256, Molecular Nutritional Regulation of Sterol Metabolism and Atherosclerosis, G4060405976, Molecular mechanism of HDL reduction in diabetic malnutrition, G478689203, G5634636492, The new function of cave-in-1 in the ABCA1-mediated HDL biogenesis, G6337455647, G6468247502, Nutritional regulation of sterol metabolism in development of lifestyle-related diseases
OpenAlex ID: W2910151691