Neutrophil-Mediated Maturation of Chemerin: A Link between Innate and Adaptive Immunity

Abstract

Dendritic cells and macrophages are professional APCs that play a central role in initiating immune responses, linking innate and adaptive immunity. Chemerin is a novel chemoattractant factor that specifically attracts APCs through its receptor ChemR23. Interestingly, chemerin is secreted as a precursor of low biological activity, prochemerin, which upon proteolytic removal of a C-terminal peptide, is converted into a potent and highly specific agonist of its receptor. Given the fact that APCs are often preceded by polymorphonuclear cells (PMN) in inflammatory infiltrates, we hypothesized that PMN could mediate chemerin generation. We demonstrate here that human degranulated PMNs release proteases that efficiently convert prochemerin into active chemerin. The use of specific protease inhibitors allowed us to identify the neutrophil serine proteases cathepsin G and elastase as responsible for this process. Mass spectrometry analysis of processed prochemerin showed that each protease generates specifically a distinct form of active chemerin, differing in their C terminus and initially identified in human inflammatory fluids. These findings strongly suggest that bioactive chemerin generation takes place during the early stages of inflammation, underscoring the functional contribution of chemerin as a bridge between innate and adaptive immunity.

Differential Patterns of Serum Concentration and Adipose Tissue Expression of Chemerin in Obesity: Adipose Depot Specificity and Gender Dimorphism

“…These conflicting results can potentially be explained by the presence of multiple chemerin-derived peptides. Whereas peptides derived from cleavage of the biologically inactive pro-chemerin by serine proteases exert chemotactic/proinflammatory activity (Wittamer et al, 2005), cysteine protease-derived peptides have anti-inflammatory effects (Cash et al, 2008). In the present study, results from the ELISA assay revealed a positive association between the circulating levels of chemerin and leptin; however, the same was not true for chemerin mRNA expression levels in adipose tissue (both subcutaneous and visceral) and circulating leptin.…”

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.…”

“…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.…”

Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis

“…These molecules with opposing activities are generated by different classes of proteases (8). Serine proteases released by granulocytes upon degranulation were shown to cleave the C-terminal extremity of pro-chemerin and to release its chemotactic potential (9). Cysteine proteases derived from activated macrophages cleave chemerin to generate potent antiinflammatory products that inhibit the production of pro-inflammatory mediators such as tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and IL-6 while inducing the expression of anti-inflammatory cytokines such as transforming growth factor-b and IL-10 (5).…”