Paper J Immunol final revised manuscript 2018
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Paper J Immunol final revised manuscript 2018
1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018leukocyte migration and3disease severity in a model of rheumatoid arthritis45Emily F. McNaughton', Andrew D. Eustace*, Sophie King*. Richard B. Sessions*, 6Alasdair Kay5, Michele Farris5, Robert Broadbridge5, Oksana Kehoe5, Andreas J. 7Kungl & Jim Middleton'89' University of Bristol, UK10ẳ Universit Paper J Immunol final revised manuscript 2018y of Keele, UKll5 Peptide Protein Research Ltd, UK12T Karl-Franzens University, Austria13^Corresponding author: email: iim.middleton@bristol.ac.uk1516Paper J Immunol final revised manuscript 2018
Author contributions: JM conceived and designed the study. EFM, ADE. SK. OK 17and AK performed experiments and analysed data. RBS assisted with peptid1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018a. EFM and JM 20wrote the manuscript.2122Funding was provided by the Biotechnology and Biological Sciences Research 23Council (BBSRC), Peptide Protein Research (PPR Ltd), Bristol Research into 24Alzheimer’s and Care of the Elderly (BRACE) and British Microcirculation Society 25(BMS).3426Abstract27In Paper J Immunol final revised manuscript 2018flammation is characterised by the infiltration of leukocytes from the circulation 28and into the inflamed area. Leukocytes are guided throughout thisPaper J Immunol final revised manuscript 2018
process by 29chemokines. These are basic proteins which interact with leukocytes to initiate their 30activation and extravasation via chemokines rece1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018ic stretch of basic amino acids on the chemokine, 33often at the C-terminus, interacts with the negatively charged GAGs which is 34considered an essential interaction for the chemokine function. Short chain peptides 35based on this GAG binding region of the chemokines CCL5, CXCL8 and CXCL12y 36were Paper J Immunol final revised manuscript 2018synthesised using standard Fmoc chemistry-. These peptides were found to bind 37to GAGs with high affinity which translated into a reduction of leukocPaper J Immunol final revised manuscript 2018
yte migration 38across a cultured human endothelial monolayer in response to chemokines. The 39leukocyte migration was inhibited upon removal of hepar1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018ding assays and to human rheumatoid arthritis (RA) 42tissue. Furthermore, control peptides lacking the basic amino acids showed reduced 43interaction with HS and no anti-chemotactic ability for leukocytes across an 44endothelial monolayer. The data suggest that the peptide competes with the wildtype Paper J Immunol final revised manuscript 2018 45(WT) chemokine for binding to GAGs such as HS and thereby reduces chemokine 46presentation and subsequent leukocyte migration. Furthermore, the leaPaper J Immunol final revised manuscript 2018
d peptide 47based on CXCL8 could reduce the disease severity and serum levels of the pro-48inflammatory cytokine TNFa in a murine antigen induced arth1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018 of site specific sequences of chemokines5651(0 target GAGs and compete with WT chemokines is a novel and promising avenue 52for the field.73https://khothuvien.cori!853Introduction5455Inflammation is a necessary process (0 prevent infection and the effects of injury on 56the body and its conclusion Paper J Immunol final revised manuscript 2018requires a controlled self-limiting process. When it 57becomes unresolved and chronic it becomes destructive leading to inflammatory 58disease. LeukocPaper J Immunol final revised manuscript 2018
yte extravasation is a characteristic of inflammation and the 59recruitment of leukocytes from the circulation into the inflamed tissue is a multi-ste1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018ll (EC) bound chemokines 62and adhesion molecules such as selectins. The interaction with chemokines activates 63leukocyte integrins enabling the leukocyte to mediate firm adhesion to the 64endothelium. Chemokines also stimulate leukocyte crawling on the endothelial 65surface and migration across th Paper J Immunol final revised manuscript 2018e ECs, the basement membrane and into the 66extracellular matrix of the tissue (2). Once within the tissue, leukocytes normally 67perform various benePaper J Immunol final revised manuscript 2018
ficial immune duties such as tissue repair and pathogen 68elimination. Due to the potentially destructive nature of leukocytes, tight regulation is 691 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l Paper J Immunol final revised manuscript 2018ding molecules: 71G-protein coupled receptors (GPCRs) and GAGs.7273Chemokines are small (8-10 kDa) chemoattractant cytokines involved in numerous 74physiological processes such as angiogenesis but mainly their role lies in the 75chemoattraction of migratory cells (3). Thus far, around 45 chemokines Paper J Immunol final revised manuscript 2018have been 76identified and are classified into four groups (C. cxc. CX3C and CC) based on the 77pattern of cysteine residues in the ligands (4). DespiPaper J Immunol final revised manuscript 2018
te the range and diversity of94https://khothuvien.cori!1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce l1 Novel anti-inflammatory peptides based on chemokines 21Novel anti-inflammatory peptides based on chemokine -2glycosaminoglycan interactions reduce lGọi ngay
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