Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

TLDR

Dendritic cells and macrophages are key antigen‑presenting cells, and the orphan GPCR ChemR23 is specifically expressed on these cells, with chemerin—a protein related to cathelicidins, cystatins, and kininogens—being a potential ligand. The study characterizes chemerin, a novel chemoattractant that signals via ChemR23 and is abundant in human inflammatory fluids. Chemerin is secreted as an inactive precursor that, upon proteolytic cleavage of its C‑terminal domain, becomes a potent ChemR23 agonist that triggers Gi‑mediated calcium release, cAMP inhibition, and MAP kinase phosphorylation. Chemerin induces calcium mobilization and chemotaxis of immature dendritic cells and macrophages in a ChemR23‑dependent manner, establishing it as a proteolytically activated, APC‑specific chemoattractant.

Abstract

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein-coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42-p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs.