Abstract
Chemerin is a multifunctional protein involved in the regulation of inflammation, metabolism, and tumorigenesis. It binds to three receptors, CMKLR1, GPR1 and CCRL2. CMKLR1 is a fully functional receptor mediating most of the known activities of chemerin. CCRL2 does not seem to couple to any intracellular signaling pathway and is presently considered as an atypical receptor able to present the protein to cells expressing CMKLR1. CCRL2 is expressed by many cell types including leukocyte subsets and endothelial cells, and its expression is strongly upregulated by inflammatory stimuli. We recently reported that chemerin can negatively regulate the angiogenesis process, including during the development of the vascular network in mouse retina. The role of CCRL2 in angiogenesis was unexplored so far. In the present work, we demonstrate that mice lacking CCRL2 exhibit a lower density of vessels in the developing retina and this phenotype persists in adulthood, in a CMKLR1-dependent manner. Vascular sprouting was not affected, while vessel pruning, and endothelial cell apoptosis were increased. Pathological angiogenesis was also reduced in CCRL2-/- mice in a model of oxygen-induced retinopathy. The phenotype closely mimics that of mice overexpressing chemerin, and the concentration of chemerin was found elevated in the blood of newborn mice, when the retinal vasculature develops. CCRL2 appears therefore to regulate the distribution and concentration of chemerin in organs, regulating thereby its bioactivity.
Highlights
C-C Motif Chemokine Receptor Like (CCRL2, known as CRAM or HCR in human and L-CCR in mouse), was first identified in 1998 as a potential chemokine receptor upregulated in murine macrophages after LPS stimulation (Fan et al, 1998; Shimada et al, 1998)
Considering the properties of chemerin in the angiogenesis process, the expression of CCRL2 by endothelial cells and its known ability to modulate the bioactivity of chemerin, we investigated whether CCRL2 could influence physiological and pathological angiogenesis using the developing mouse retina as a model
Considering the role played by chemerin during the development of the vascular network in the post-natal mouse retina, we investigated the potential role of the non-functional chemerin receptor, CCRL2, in the same process
Summary
C-C Motif Chemokine Receptor Like (CCRL2, known as CRAM or HCR in human and L-CCR in mouse), was first identified in 1998 as a potential chemokine receptor upregulated in murine macrophages after LPS stimulation (Fan et al, 1998; Shimada et al, 1998). CCRL2 is expressed in most leukocyte populations, including monocytes, macrophages, DCs, neutrophils, CD4+ and CD8+ T cells, B cells, NK cells, and mast cells (Brouwer et al, 2004; Oostendorp et al, 2004; Zabel et al, 2008; Otero et al, 2010). To the atypical chemokine receptors ACKR1 (DARC) and ACKR2 (D6), CCRL2 lacks the DRYLAIV motif that is essential for G protein coupling and chemotactic responses (Shimada et al, 1998)
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