Role of neutrophil proteinase 3 and mast cell chymase in chemerin proteolytic regulation

Abstract

Chemerin is a potent chemotactic factor that was identified recently as the ligand of ChemR23, a G protein-coupled receptor expressed by mononuclear phagocytes, dendritic cells (DCs), and NK cells. Chemerin is synthesized as a secreted precursor, prochemerin, which is poorly active on ChemR23. However, prochemerin can be converted rapidly into a full ChemR23 agonist by proteolytic removal of a carboxy-terminal peptide. This maturation step is mediated by the neutrophil-derived serine proteases elastase and cathepsin G. In the present work, we have investigated proteolytic events that negatively control chemerin activity. We demonstrate here that neutrophil-derived proteinase 3 (PR3) and mast cell (MC) chymase are involved in the generation of specific chemerin variants, which are inactive, as they do not induce calcium release or DC chemotaxis. Mass spectrometry analysis showed that PR3 specifically converts prochemerin into a chemerin form, lacking the last eight carboxy-terminal amino acids, and is inactive on ChemR23. Whereas PR3 had no effect on bioactive chemerin, MC chymase was shown to abolish chemerin activity by the removal of additional amino acids from its C-terminus. This effect was shown to be specific to bioactive chemerin (chemerin-157 and to a lesser extent, chemerin-156), as MC chymase does not use prochemerin as a substrate. These mechanisms, leading to the production of inactive variants of chemerin, starting from the precursor or the active variants, highlight the complex interplay of proteases regulating the bioactivity of this novel mediator during early innate immune responses.

Development by Genetic Immunization of Monovalent Antibodies (Nanobodies) Behaving as Antagonists of the Human ChemR23 Receptor

“…However, prochemerin is expressed constitutively by different tissues in noninflammatory conditions, and its bioactivity depends primarily on the complex proteolytic processing of its C terminus. Numerous proteases belonging to different classes and involved in various pathways were described to regulate chemerin bioactivity (14,(35)(36)(37)(38)(39), rendering the regulation of this system particularly complex. In addition, ChemR23 expression was described in many cell populations other than leukocytes, including preadipocytes and adipocytes (5,6), skeletal muscle cells (9), and endothelial cells (10), and additional roles for the chemerin/ChemR23 system were proposed in the control of lipid and glucose metabolism (9,17,40), blood pressure (41), and angiogenesis (10).…”

Chemerin as an independent predictor of cardiovascular event risk

“…Chemerin bioactivity is related to only one function or signal pathway (and is therefore relative) according to most of the studies. Whether single chemerin isoforms have distinctive bioactivity in multiple pathways or functions is not yet clearly known [Zabel et al 2004;Guillabert et al 2008] (Figure 1). …”

“…Thus, further characterization of chemerin-isoform generation is necessary in order to fully understand the local chemerin bioactivity and the biological functions of chemerin [Guillabert et al 2008].…”

“…Different patterns of chemerin isoforms are produced in vivo in human blood , acid (Chem-157), synovial fluid (Chem-158), and cerebrospinal fluid (Chem-158). All proteases play a role in the regulation of chemerin activity via the C-terminal branch [Guillabert et al 2008].…”

Cloning of porcine chemerin, ChemR23 and GPR1 and their involvement in regulation of lipogenesis

“…Under certain conditions such as coagulation, fibrinolytic, inflammatory and complement cascades, prochemerin could be converted into active form by serine proteases existing in the surrounding microenvironment (6,7). Prochemerin and active chemerin may be disabled by other diverse serine proteases (8) or processed by cysteine proteases into an anti-inflammatory form that inhibit the expression of proinflammatory cytokines stimulated by LPS in a ChemR23-dependent manner (9). Several recent studies have highlighted the involvement of chemerin in obesity, inflammation and metabolic syndromes (10)(11)(12).…”