Up‐regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis

Abstract

Objective. Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation.Methods. Expression of CCRL2 on joint-infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase-polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48-well chamber.Results. CCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with lipopolysaccharide (1 g/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokinestimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF.Conclusion. CCRL2 expression is up-regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA.

Functional and genomic changes induced by alveolar transmigration in human neutrophils

“…The largest induction was observed for the orphan chemokine receptor CCRL2, which increased 168-fold. CCRL2 increases 12.6-fold upon in vitro endotoxin stimulation as has been previously described (12) and is one of a cluster of chemokine receptor genes on 3p21. Three other members of this cluster, CCR1, CCR5, and CXCR6, also exhibited increased expression (4.7-, 5.5-, and 3.6-fold, respectively) in air space neutrophils; however, other members of the cluster (CCR2 and CCR3) are unaffected.…”

Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus

“…SLE. [34][35][36] Given that the complex network of cytokines and imbalance of Th1 and Th2 immune responses may contribute to the pathogenesis and activation of SLE, studies on chemokines and T cell expression of chemokine receptors have shed lights on the underlying mechanisms causing the immune dysregulation, such as inappropriate T cell activation or trafficking in this disease. 21 37 However, there are few reports addressing the balance of these Th1 or Th2 chemoattractants, nor the possible influence of proinflammatory cytokines such as IL18 on chemokine expressions.…”

Interferon-α and -β differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression

“…Finally, the orphan chemokine receptor CCRL2 (Table 2), which has considerable homology to CCR2, remains a candidate to mediate the CXCL11 inhibitory effect. The expression of CCRL2 is up-regulated in leukocytes that infiltrate the joints of patients with rheumatoid arthritis, a disease characterized by the destruction of cartilage and bone, in which osteoclasts have a major role (35). Furthermore, CCL2, the agonist ligand of CCR2, plays an essential function in the in vitro fusion of adherent peripheral blood mononuclear cells, a necessary step in osteoclast formation (36).…”