Chemerin Activation by Serine Proteases of the Coagulation, Fibrinolytic, and Inflammatory Cascades

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.A network of serine proteases regulates the primary response to injury and infection in the host. Serine proteases of the coagulation and fibrinolytic cascades mediate the homeostatic response to blood vessel injury. Kallikrein and factor XIIa process kininogens to generate bradykinin, a potent vasodilator that triggers increased vascular permeability during inflammation. Serine proteases termed convertases release multiple pathogen-neutralizing components of activated complement. Serine protease cascades also regulate the recruitment of phagocytic and antigen-presenting cells to sites of inflammation and tissue damage. The complement cascade, for example, releases active components C5a and C3a, potent attractants for many leukocytes, including neutrophils and monocytes (1, 2). Thus serine proteases are critical participants in rapid defense mechanisms in the body.We and others have recently identified chemerin as a potent chemoattractant for cells expressing the G-protein-linked receptor chemokine-like receptor 1 (CMKLR1), 5 also known as ChemR23 or DEZ (3-5). CMKLR1 is expressed in vitro by monocyte-derived macrophages and dendritic cells (3,5,6) and in vivo by circulating plasmacytoid dendritic cells (pDCs) (5) and tissue macrophages.6 pDCs are major producers of ␣-interferons and can differentiate into antigen-presenting cells capable of triggering T effector or suppressor responses (7). Tissue macrophages have a major role as phagocytes but, similar to pDCs, are also implicated in bridging innate and adaptive immune responses and in regulating immunity in sterile versus infectious tissue injury (8). Importantly, chemerin is widely expressed and circulates in human plasma in an inactive state (5). Active forms of chemerin have been isolated from hu...

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

“…Fourth, active chemerin accumulates in SspB-treated plasma despite an abundance of various inhibitors that keep host-derived proteases under the tight control. Importantly, host proteases implicated thus far as chemerin activators, such as neutrophil elastase, cathepsin G, plasmin, urokinase-type plasminogen activator, and tissue plasminogen activator (9,10) would be expected to be opposed by plasma inhibitors, including ␣1-protease inhibitor, ␣1-antichymotrypsin, ␣2-antiplasmin, and plasminogen activator inhibitor (30 -32). At early stages of acute inflammation, the protease-antiprotease balance likely shifts in favor of proteolysis.…”

“…After a Ͼ100-fold buffer exchange into 50 mM HEPES, 0.3 M NaCl (pH 8.0), prochemerin was purified by running the solution over nickel-nitrilotriacetic acid (Amersham Biosciences) and C-18 reverse-phase HPLC columns (Vydac). The protein was lyophilized and checked for purity using electrospray mass spectrometry (9).…”

“…Chemerin mRNA is present in most tissues, including liver, pancreas, and skin (7,8). The liver, however, appears to be a primary source of chemerin, and is likely to be responsible for the high levels of this protein in plasma (8,9). Chemerin circulates as an inactive precursor (prochemerin) in blood and requires proteolytic processing for activation.…”

“…Chemerin circulates as an inactive precursor (prochemerin) in blood and requires proteolytic processing for activation. Recently, we and others have demonstrated that active chemerin is generated by serine proteases of the inflammatory, coagulation and fibrinolytic cascades (9,10). These include neutrophil-derived elastase and cathepsin G, mast cell tryptase, as well as factors VIIa, XIIa, tissue plasminogen activator, urokinase-type plasminogen activator, and plasmin.…”

La chémérine

“…Dans tous les cas, de faibles taux de chémérine S157 ont été retrouvés [2]. Dans la littérature, les concentrations plasmatique et sérique de la chémérine varient entre 3 et 4,4 nM chez l'homme [3,4] et 0,5 à 0,6 nM chez la souris [5]. L'homologie de séquence primaire de la chémérine humaine avec celle du porc est de 84 %, 79 % avec le bovin, 66 % avec le rat et 63 % avec la souris [6].…”