Absence of the Non-Signalling Chemerin Receptor CCRL2 Exacerbates Acute Inflammatory Responses In Vivo

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.

The complex role of adipokines in obesity, inflammation, and autoimmunity

“…This receptor is also engaged in the regulation of immune cell recruitment, to dampen an acute inflammatory response. Mice that lack CCRL2 have an exacerbated acute inflammatory response to peritonitis and have increased neutrophils and monocytes in the peritoneal cavity [200].…”

Molecular Basis for CCRL2 Regulation of Leukocyte Migration

“…Taken together, these results support a role for CCRL2 in the regulation of CXCR2-mediated inside-out β2-integrin activation ( Del Prete et al, 2017 ). Using different models of acute inflammation induced by zymosan and thioglycolate, Regan-Komito et al (2017) reported that Ccrl2-deficient mice expressed an exacerbated phenotype characterized by increased neutrophils infiltration associated to increased local and systemic levels of chemerin and CXCL1. It is possible that different experimental conditions might be responsible for this apparently contrasting phenotype.…”

Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

“…Zymosan induced peritonitis (using 100 ug of zymosan) is a model of acute inflammation characterised by the recruitment of myeloid cells to the peritoneum following injection of zymosan, that is largely resolved after 48-96 h (Regan-Komito et al, 2017). To test if pharmacological inhibition of BTK with the FDA/EMA approved BTK inhibitor ibrutinib would reduce myeloid cell recruitment during acute inflammation C57BL/6 mice were pre-treated with ibrutinib (0.1 -10 mg/kg; p.o.)…”