Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis

Alison Cartwright,Caroline Schmutz,Ayman Askari,Jan-Herman Kuiper,Jim Middleton

doi:10.1016/j.cyto.2014.02.015

Abstract

Chemokine receptors on leukocytes mediate the recruitment and accumulation of these cells within affected joints in chronic inflammatory diseases such as rheumatoid arthritis (RA). Identification of involved receptors offers potential for development of therapeutic interventions. The objective of this study was to investigate the expression of orphan receptor GPR15/BOB in the synovium of RA and non-RA patients and in peripheral blood of RA patients and healthy donors.GPR15/BOB protein and messenger RNA expression were examined in RA and non-RA synovium by immunofluorescence and reverse-transcription polymerase chain reaction (RT-PCR) respectively. GPR15/BOB expression on peripheral blood leukocytes was analysed by flow cytometry and GPR15/BOB messenger RNA was examined in peripheral blood monocytes by RT-PCR.GPR15/BOB protein was observed in CD68+ and CD14+ macrophages in synovia, with greater expression in RA synovia. GPR15/BOB protein was expressed in all patient synovia whereas in non-RA synovia expression was low or absent. Similarly GPR15/BOB messenger RNA was detected in all RA and a minority of non-RA synovia. GPR15/BOB protein was expressed on peripheral blood leukocytes from RA and healthy individuals with increased expression by monocytes and neutrophils in RA. GPR15/BOB messenger RNA expression was confirmed in peripheral blood monocytes.In conclusion GPR15/BOB is expressed by macrophages in synovial tissue and on monocytes and neutrophils in peripheral blood, and expression is up-regulated in RA patients compared to non-RA controls. This orphan receptor on monocytes/macrophages and neutrophils may play a role in RA pathophysiology.

Highlights

In rheumatoid arthritis (RA) the synovial membrane undergoes infiltration by monocytes/macrophages, T cells and B cells, and neutrophils accumulate in the synovial fluid, and these cells are centrally involved in disease mechanisms [1,2,3,4]
Leukocytes including macrophages are recruited by the action of chemoattractant cytokines secreted within the synovium by both resident and infiltrated cells [4]
In this study we demonstrated that the GPR15/BOB receptor was expressed by macrophages in synovial tissue with up-regulation in RA tissue

Summary

Introduction

In rheumatoid arthritis (RA) the synovial membrane undergoes infiltration by monocytes/macrophages, T cells and B cells, and neutrophils accumulate in the synovial fluid, and these cells are centrally involved in disease mechanisms [1,2,3,4]. GPR15/BOB is an orphan chemokine receptor whose natural ligand is unknown. It was found by expression cloning of simian immunodeficiency virus (SIV) receptors which isolated two genes encoding G protein-coupled receptors (GPCRs). These proteins were named Bonzo (STRL33/CXCR6) and BOB (brother of Bonzo) and presented similarities to chemokine receptors [5]. BOB is 360 amino acids in size and is identical to the previously cloned orphan receptor, GPR15.

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