Up-regulated expression and activation of CCRL2 in RA

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Arthritis Rheum. 2004 Jun;50(6):1806-14.

Up-regulated expression and activation of the orphan chemokine receptor,

CCRL2, in rheumatoid arthritis.

Galligan CL, Matsuyama W, Matsukawa A, Mizuta H, Hodge DR, OM,

Yoshimura T.

National Cancer Institute at Frederick, Frederick, land 21702, USA.

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 microg/ml) or tumor

necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were

expressed in cytokine-stimulated 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.

PMID: 15188357

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