Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease and is characterized by infiltration of macrophages and neutrophils into the joint space. A chemokine receptor, CC chemokine receptor (CCR) 2, is expressed on macrophages infiltrating into the synovium of RA patients, but the roles of CCR2-mediated signals in RA still remain controversial. We demonstrated that ablation of Ccr2 gene aggravated the polyarthritis, which develops in interleukin-1 receptor antagonist (IL-1ra)-deficient mice. This is associated with augmented neutrophil infiltration and osteoclastogenesis. Due to the important role of the CCR2-mediated signals in the egress of monocytes from bone marrow, Ccr2 gene ablation resulted in increased number of monocytes, a precursor of osteoclasts, in bone marrow of IL-1ra-deficient mice. Intraarticular neutrophils expressed the receptor of activator of NF-κB ligand (RANKL) and a disintegrin and metalloproteinase (ADAM) 8, the factors which are crucially involved in osteoclast formation. Additional blockade of neutrophil infiltration decreased the numbers of osteoclasts and attenuated arthritis in IL-1ra-CCR2-double deficient mice. These observations revealed that CCR2-mediated signals can modulate arthritis development and progression by suppressing the egress of monocytes, a precursor of osteoclasts and promoting the infiltration of neutrophils, a rich source of osteoclastogenic factors.
