Abstract
Proteases function at every level in host defense, from regulating vascular hemostasis and inflammation to mobilizing the "rapid responder" leukocytes of the immune system by regulating the activities of various chemoattractants. Recent studies implicate proteolysis in the activation of a ubiquitous plasma chemoattractant, chemerin, a ligand for the G-protein-coupled receptor CMKLR1 present on plasmacytoid dendritic cells and macrophages. To define the pathophysiologic triggers of chemerin activity, we evaluated the ability of serum- and inflammation-associated proteases to cleave chemerin and stimulate CMKLR1-mediated chemotaxis. We showed that serine proteases factor XIIa and plasmin of the coagulation and fibrinolytic cascades, elastase and cathepsin G released from activated neutrophil granules and mast cell tryptase are all potent activators of chemerin. Activation results from cleavage of the labile carboxyl terminus of the chemoattractant at any of several different sites. Activation of chemerin by the serine protease cascades that trigger rapid defenses in the body may direct CMKLR1-positive plasmacytoid dendritic cell and tissue macrophage recruitment to sterile sites of tissue damage, as well as trafficking to sites of infectious and allergic inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Baculoviridae / genetics
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Binding Sites
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Cathepsin G
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Cathepsins / chemistry
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Cathepsins / pharmacology
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Chemokines / chemistry*
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Chemotaxis
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Culture Media, Conditioned / pharmacology
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Culture Media, Serum-Free / pharmacology
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Dendritic Cells / cytology
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Escherichia coli / metabolism
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Factor XIIa / chemistry
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Fibrinolysin / chemistry
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Fibrinolysin / metabolism
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Humans
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Inflammation
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Intercellular Signaling Peptides and Proteins
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Ligands
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Macrophages / cytology
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Macrophages / metabolism
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Mass Spectrometry
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Mast Cells / cytology
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Models, Biological
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Molecular Sequence Data
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Neutrophils / metabolism
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Pancreatic Elastase / chemistry
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Pancreatic Elastase / metabolism
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Plasmacytoma / metabolism
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Serine Endopeptidases / chemistry*
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Serine Endopeptidases / pharmacology
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Time Factors
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Transfection
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Trypsin / chemistry
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Tryptases
Substances
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Chemokines
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Culture Media, Conditioned
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Culture Media, Serum-Free
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Intercellular Signaling Peptides and Proteins
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Ligands
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RARRES2 protein, human
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Recombinant Fusion Proteins
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Cathepsins
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Serine Endopeptidases
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CTSG protein, human
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Cathepsin G
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Pancreatic Elastase
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Factor XIIa
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Trypsin
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Tryptases
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Fibrinolysin