Proinflammatory Action of a New Electronegative Low-Density Lipoprotein Epitope.
Tanize do Espirito Santo FaulinSoraya Megumi KazumaGustavo Luis TripodiMarcela Frota CavalcanteFelipe WakasuquiCristiano Luis Pinto OliveiraMaximilia Frazão de Souza DegenhardtJussara MichaloskiRicardo Jose GiordanoDaniel Francisco Jacon KetelhuthDulcineia Saes Parra AbdallaPublished in: Biomolecules (2019)
The electronegative low-density lipoprotein, LDL (-), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (-) were mapped using a phage display library of peptides and monoclonal antibodies reactive to this modified lipoprotein. Two different peptide libraries (X6 and CX8C for 6- and 8-amino acid-long peptides, respectively) were used in the mapping. Among all tested peptides, two circular peptides, P1A3 and P2C7, were selected based on their high affinities for the monoclonal antibodies. Small-angle X-ray scattering analysis confirmed their structures as circular rings. P1A3 or P2C7 were quickly internalized by bone marrow-derived murine macrophages as shown by confocal microscopy. P2C7 increased the expression of TNFα, IL-1 β and iNOS as well as the secretion of TNFα, CCL2, and nitric oxide by murine macrophages, similar to the responses induced by LDL (-), although less intense. In contrast, P1A3 did not show pro-inflammatory effects. We identified a mimetic epitope associated with LDL (-), the P2C7 circular peptide, that activates macrophages. Our data suggest that this conformational epitope represents an important danger-associated molecular pattern of LDL (-) that triggers proinflammatory responses.
Keyphrases
- low density lipoprotein
- amino acid
- high resolution
- nitric oxide
- endothelial cells
- rheumatoid arthritis
- poor prognosis
- magnetic resonance
- single molecule
- monoclonal antibody
- pseudomonas aeruginosa
- molecular dynamics
- mass spectrometry
- electronic health record
- dendritic cells
- immune response
- vascular endothelial growth factor
- long non coding rna
- cystic fibrosis
- deep learning
- big data
- artificial intelligence
- anti inflammatory
- dual energy