Nonredundant role of CCRL2 in lung dendritic cell trafficking

Abstract

IntroductionDendritic cells (DCs) are professional antigen-presenting cells and key regulators of T-cell functions. 1,2 In the airway epithelium, DCs form an extensive network, where they continuously sense environmental antigens. After antigen capture, lung DCs migrate to mediastinal lymph nodes, where antigens are presented to T cells. Activation of a T helper cell 2 (Th2)-skewed response by airway DCs is responsible for allergic immune responses in the lung. 3,4 Chemokine receptors play a crucial role in the migration of maturing DCs to secondary lymphoid organs, 5,6 and several studies have shown that this process is a crucial event for the appropriate activation of the immune response. 7-10 DC migration to lymph nodes relies on the functional expression of CCR7 5,6 as well as other chemotactic receptors, such as CCR8 and BLT1. [9][10][11] In addition, lung DC migration is also regulated by PD1, one of the 2 PGD2 receptors, and by the transcription factors PPR␥ and Runx3. [12][13][14] However, as a difference from DCs localized in other anatomical compartments, the homing of lung DCs to lymph nodes is independent of the action of MRP1, the LTC4 transporter that regulates CCR7 functions. 11 This finding indicates that DC trafficking is regulated in a tissue-specific manner.Chemokine CC motif receptor-like 2 (CCRL2), also known as L-CCR (lipopolysaccharide [LPS]-inducible CC chemokinerelated gene and Eo1), is a heptahelic serpentine receptor that shares the highest homology with the chemokine receptors, CCR1 and CCR5. CCRL2 is structurally characterized by the presence of a noncanonical DRYLAIV motif. CCRL2 was originally identified in the mouse macrophage cell line RAW 264.7 15 and was recently reported to bind the chemotactic protein chemerin, though in the absence of any detectable intracellular signaling. 16 CCRL2 expression at the mRNA level has been described in murine macrophages, 15 glial cells, astrocytes, and microglia stimulated with LPS 17,18 and in mast cells. 16 CCRL2 was also reported to be up-regulated in lung macrophages and epithelial cells after in vivo sensitization. 19 The human gene most closely related to CCRL2 is HCR with its 2 splicing variants, CRAM-A and CRAM-B.Here, we describe that CCRL2 is rapidly induced during mouse DC maturation with a kinetics that precedes CCR7 induction. To evaluate the relevance of this receptor in DC biology, we generated CCRL2-deficient mice and used them in an established model of allergen-induced airway inflammation, in which DCs are known to play a crucial role. 20 The results reported here highlight a nonredundant role for CCRL2 in the migration of lung DCs to regional lymph nodes and in the induction of Th2-oriented airway allergic inflammation. These results propose CCRL2 as a new potential target for therapeutic strategies aimed at controlling lung hypersensitivity. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this ...

Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation

“…CCL4 is also reported to be a chemoattractant of macrophages, monocytes, dendritic cells, natural killer cells, and eosinophils [32]. Likewise, Ccrl2 −/− mice have been reported to have a reduced inflammatory response in lung tissue following OVA-induced airway inflammation [33].…”

Endothelial Cell–Derived Chemerin Promotes Dendritic Cell Transmigration

“…The 1G11 cells were stimulated with RA (5 mM) or with IFN-g/TNF-a/LPS (50 ng/ ml, 20 ng/ml, 1 mg/ml, respectively) for 18 h. After Fc blocking, the cells were stained with an anti-CCRL2 mAb (28), washed with PBS (Life Technologies), and then incubated with an anti-mouse Alexa 488 mAb (Invitrogen, Life Technologies, Monza, Italy). Samples were read on a Particle Analysing System cytofluorimeter (Partec, Muenster, Germany), and results were analyzed by FlowJo software (Tree Star).…”

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

“…Lmr loci on chromosomes 2 and 11 detected in a cross between CcS-9 and BALB/c overlap with loci Lmr14 [91–93] and Lmr15 [91, 93] detected in cross of CcS-16 with BALB/c, and were therefore given the same name. Abbreviations show genes that have been reported to be involved in eosinophil functions: Bcl2l1 (BCL2-like 1) [78], Ccl11 (chemokine (C-C motif) ligand 11) [79] Ccl3 (chemokine (C-C motif) ligand 3) [79], Ccl5 (chemokine (C-C motif) ligand 5) [79], Ccl7 (chemokine (C-C motif) ligand 7) [79], Ccl8 (chemokine (C-C motif) ligand 8) [80], Ccrl2 (chemokine (C-C motif) receptor-like 2) [81], Cish (cytokine inducible SH2-containing protein) [82], Gnai2 (guanine nucleotide binding protein (G protein), alpha inhibiting 2) [83], Hck (hemopoietic cell kinase) [84], Hmgb1 (high mobility group box 1) [85], Il13 (interleukin 13) [86], Il3 (interleukin 3) [87], Il4 (interleukin 4) [88], Il5 (interleukin 5) [89], and Nlrp3 (NLR family, pyrin domain containing 3) [90]. However, the effects of eosinophil controlling loci might be caused by genes that are at the present not considered as candidates …”