Abstract
Chemerin is a chemotactic protein that induces migration of several immune cells including macrophages, immature dendritic cells, and NK cells. Chemerin binds to three G protein-coupled receptors (GPCRs), including CCRL2. The exact function of CCRL2 remains unclear. CCRL2 expression is rapidly upregulated during inflammation, but it lacks the intracellular DRYLAIV motif required for classical GPCR downstream signalling pathways, and it has not been reported to internalise chemerin upon binding. The aim of this study was to investigate what role if any CCRL2 plays during acute inflammation. Using the zymosan- and thioglycollate-induced murine models of acute inflammation, we report that mice deficient in the Ccrl2 gene display exaggerated local and systemic inflammatory responses, characterised by increased myeloid cell recruitment. This amplified myeloid cell recruitment was associated with increased chemerin and CXCL1 levels. Furthermore, we report that the inflammatory phenotype observed in these mice is dependent upon elevated levels of endogenous chemerin. Antibody neutralisation of chemerin activity in Ccrl2−/− mice abrogated the amplified inflammatory responses. Importantly, chemerin did not directly recruit myeloid cells but rather increased the production of other chemotactic proteins such as CXCL1. Administration of recombinant chemerin to wild-type mice before inflammatory challenge recapitulated the increased myeloid cell recruitment and inflammatory mediator production observed in Ccrl2−/− mice. We have demonstrated that the absence of CCRL2 results in increased levels of local and systemic chemerin levels and exacerbated inflammatory responses during acute inflammatory challenge. These results further highlight the importance of chemerin as a therapeutic target in inflammatory diseases.
Highlights
Understanding the endogenous pathways that regulate inflammatory responses is of critical importance for the development of novel therapies for chronic inflammatory disease
To interrogate this in our model of acute inflammation, we quantified total chemerin levels in the peritoneum during this acute inflammatory response and found that levels were significantly increased compared with naïve mice 4 h following zymosan challenge (2.5 ± 0.4 ng/ml at 4 h compared with 1.2 ± 0.3 ng/ml in naïve mice) (Figure 1B)
When we measured mediator levels in the peritoneum of these mice, we observed a twofold reduction in CXCL1 levels in the anti-chemerin treated mice compared with isotype control treated mice and no differences in IL-6 levels between the groups (Figures 5G,H). These results indicate that the elevated chemerin levels observed in Ccrl2−/− mice contribute to the exaggerated leucocyte recruitment as well as the elevated CXCL1 levels observed in these mice during acute inflammation
Summary
Understanding the endogenous pathways that regulate inflammatory responses is of critical importance for the development of novel therapies for chronic inflammatory disease. It is appreciated that there exists a plethora of lipid mediators as well as other immune modulating proteins and peptides that play important roles during both the onset as well as the resolution of inflammation [6,7,8]. A number of lipid mediators including the resolvins, lipoxins, maresins, and protectins have been more recently come to the fore [7, 8]. These novel immune modulatory mediators and others may represent new avenues to explore for the treatment of chronic inflammatory disease
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