Human articular chondrocytes express ChemR23 and chemerin; ChemR23 promotes inflammatory signalling upon binding the ligand chemerin21-157

Abstract

IntroductionChemerin is a chemotactic peptide which directs leukocytes expressing the chemokine-like receptor ChemR23 towards sites of inflammation. ChemR23 is a G protein-coupled receptor which binds several different ligands, and it is also expressed by other cell types such as adipocytes. In addition to chemotaxis, recent reports suggest that ChemR23 is capable of mediating either inflammatory or anti-inflammatory effects, depending on the type of ligand it binds. In the present study, we aimed to clarify whether human chondrocytes express ChemR23 and chemerin, and whether chemerin/ChemR23 signalling could affect secretion of inflammatory mediators.MethodsTissue sections were taken from human knee joints and labelled with antibodies towards chemerin and ChemR23. Chondrocytes from cartilage tissue were isolated, cultured and assessed for chemerin and ChemR23 expression by PCR and immunolabelling. Receptor activation and intracellular signalling were studied by assessment of phosphorylated mitogen activated protein kinases (MAPKs) and phosphorylated Akt after stimulating cells with recombinant chemerin21-157. Biological effects of chemerin21-157 were investigated by measuring secretion of pro-inflammatory cytokines and metalloproteases in cell supernatants.ResultsBoth serially cultured human articular chondrocytes and resident cells in native cartilage expressed chemerin and ChemR23. Stimulating cells with chemerin21-157 resulted in phosphorylation of p44/p42 MAPKs (ERK 1/2) and Akt (Ser 473). Also, significantly enhanced levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-8 and MMP-13 were detected.ConclusionsThese results demonstrate that human chondrocytes express both the receptor ChemR23 and the ligand chemerin. Chemerin21-157 stimulation engaged signal-transduction pathways that further promoted inflammatory signalling in chondrocytes, as judged by an enhanced secretion of cytokines and metalloproteases. Taken together, the previously reported chemotaxis and the present findings suggest that the receptor and its ligand may play pivotal roles in joint inflammation.

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

“…In contrast, we and others (14) show that ChemR23 mRNA levels increase in human monocytes and macrophages after stimulation with LPS or the inflammatory cytokines TNF-a and IFN-g, suggesting that there are differences between mouse and human in the regulation and eventual function of ChemR23. This notion would be supported by the fact that chemerin has ChemR23-dependent antiinflammatory and protective effects in some mouse models of inflammation (39,40), whereas in humans, chemerin was shown to induce inflammatory signaling in chondrocytes (41) and increased chemerin concentrations were associated with pathologies connected with chronic and systemic inflammation (19,21,(42)(43)(44). The differential expression pattern of ChemR23 on stimulated macrophages and the possible opposite effect of chemerin on inflammation between mouse and human may indicate that the role of ChemR23 signaling differs between the two species.…”

Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

“…Here, chemerin stimulates angiogenesis (Bozaoglu et al, 2010;Kaur et al, 2010), matrix metalloproteinase (MMP) activity and cell survival (Kaur et al, 2010). In chondrocytes which also express CMKLR1 chemerin induces production of proinflammatory cytokines and MMP13 (Berg et al, 2010). However, the effect of chemerin on hepatocytes has not been studied so far.…”

The Adipokine Chemerin Induces Apoptosis in Cardiomyocytes

“…Several studies have investigated the effects of chemerin treatment on AKT phosphorylation: chemerin increases phosphorylation of Ser473 in both human umbilical vein endothelial cells, leading to the activation of endothelial nitric oxide synthase and increased nitric oxide [21,22], and in human articular chondrocytes, promoting inflammatory signalling [23]; on the other hand, it decreases phosphorylation at Thr308 in both human skeletal muscle cells (in which Ser473 phosphorylation is also decreased) [24,25] and, in vivo, in mouse skeletal muscle [26], leading in both cases to insulin resistance. Zhang et al (2014) have recently found that chemerin diminished the glucose uptake by rat cardiomyocytes, and suggested that this effect could be mediated by a negative influence of chemerin on AKT phosphorylation [59], other authors have found that in skeletal muscle of mice chemerin treatment decreased the insulin-stimulated AKT phosphorylation, produced alterations in the mitochondrial function and increased oxidative stress, with implications in the regulation of insulin resistance [57].…”