Endothelial Cell–Derived Chemerin Promotes Dendritic Cell Transmigration

Abstract

ChemR23 is a chemotactic receptor expressed by APCs, such as dendritic cells, macrophages, and NK cells. Chemerin, the ChemR23 ligand, was detected by immunohistochemistry, to be associated with inflamed endothelial cells in autoimmune diseases, such as lupus erythematosus, psoriasis, and rheumatoid arthritis. This study reports that blood and lymphatic murine endothelial cells produce chemerin following retinoic acid stimulation. Conversely, proinflammatory cytokines, such as TNF-α, IFN-γ, and LPS, or calcitriol, are not effective. Retinoic acid–stimulated endothelial cells promoted dendritic cell adhesion under shear stress conditions and transmigration in a ChemR23-dependent manner. Activated endothelial cells upregulated the expression of the atypical chemotactic receptor CCRL2/ACKR5, a nonsignaling receptor able to bind and present chemerin to ChemR23+ dendritic cells. Accordingly, activated endothelial cells expressed chemerin on the plasma membrane and promoted in a more efficient manner chemerin-dependent transmigration of dendritic cells. Finally, chemerin stimulation of myeloid dendritic cells induced the high-affinity binding of VCAM-1/CD106 Fc chimeric protein and promoted VCAM-1–dependent arrest to immobilized ligands under shear stress conditions. In conclusion, this study reports that retinoic acid–activated endothelial cells can promote myeloid and plasmacytoid dendritic cell transmigration across endothelial cell monolayers through the endogenous production of chemerin, the upregulation of CCRL2, and the activation of dendritic cell β1 integrin affinity.

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

“…Promoter P2 is therefore likely to be used in cell types other than monocytes and macrophages. In this line, endothelial cells express ChemR23 and secrete chemerin upon retinoic acid stimulation, which was shown to facilitate dendritic cell transmigration (49).…”

Role of Atypical Chemokine Receptors in Microglial Activation and Polarization

“…However, these results were not subsequently confirmed by other groups (Del Prete et al, 2013; De Henau et al, 2016). CCRL2 binds and presents chemerin, a non-chemokine chemotactic protein, to adjacent cells expressing the functional chemerin receptor ChemR23, and acts as regulator of chemerin bioavailability (Zabel et al, 2008; Gonzalvo-Feo et al, 2014). Neither internalization nor calcium mobilization was described upon chemerin binding (Zabel et al, 2008).…”

“…Neither internalization nor calcium mobilization was described upon chemerin binding (Zabel et al, 2008). CCRL2 is expressed by endothelial and epithelial cells, and by a variety of leukocytes, including macrophages, dendritic cells, mast cells and neutrophils and its expression is increased by pro-inflammatory stimuli (Galligan et al, 2004; Zabel et al, 2008; Otero et al, 2010; Monnier et al, 2012; Del Prete et al, 2013; Gonzalvo-Feo et al, 2014). In particular, CCRL2 was described to play a non-redundant role in the regulation of dendritic cell migration during airway inflammation (Otero et al, 2010).…”

Overview and potential unifying themes of the atypical chemokine receptor family

“…Conflicting data have been reported on the ability of this receptor, which is strongly induced by proinflammatory stimuli (LPS, IFN-g, TNF-a) [34][35][36][37] and retinoic acid [38], to bind the homeostatic chemokine CCL19 and the inflammatory chemokine CCL5 [35,[39][40][41]. Moreover, the nonchemokine ackr5 ligand chemerin, which binds the receptor with high affinity, without triggering intracellular calcium mobilization and chemotaxis [42], is detected in healthy subject plasma and is up-regulated in many inflammatory conditions [38]. Taken together, results suggest that ACKR3 and ackr5 are involved in biologic functions outside of the chemokine system, similar to some conventional chemokine receptors [43].…”