Monocyte chemotactic protien-1 (MCP-1/CCL2) and its high affinity receptor CCR2 play a critical role in leukocyte migration and the generation of inflammatory response. The role of MCP-1/CCR2 axis in resolution of inflammation has not been explored. In three different murine models of arthritis I have shown that genetic inactivation of the CC chemokine receptor (CCR)2 leads to a more severe chronic persistent arthritis. Genetic inactivation of CCR2 results not only in substantial disruptions in Dendritic Cells (DC) and monocyte migration, but also, the CCR2 null state is characterized by the loss of a subtype of DCs implicated in the generation of tolerance. We surmised that because DC and monocytes play critical roles in the different phases of RA and CIA, defects in these cell types occurring as part of the CCR2 null state may greatly contribute to the more severe arthritic phenotype seen in CCR2 KO mice. Thus, in this application we will focus on teasing apart the potential mechanisms by which CCR2 modulates arthritis. To do so we will address the following two Specific Aims :
Aim #1 will test the hypothesis that the regulatory role of CCR2 in experimental arthritis is mediated in part via its effects on DCs and/or monocyte macrophage biology.
Aim #2 will test the hypothesis that CCR2-dependent cellular processes modulate the kinetics of arthritogenic antibodies deposition and /or clearance. The studies proposed are significant because they will capitalize on our expertise in immunology, chemokine biology and small animal imaging to fill important knowledge gaps in RA pathogenesis, and they are relevant because they address a critical area in chemokine biology with potential therapeutic implications, namely the pathogenic link between CCR2 and RA pathogenesis. The proposed research is innovative because it utilizes state-of-the-art techniques using MicroSPECT, PET and CT imaging for small animals. Rheumatoid Arthritis affects 1% of US population, and therapies designed to block CCR2 are in phase II clinical trials. Thus information obtained from proposed studies which explore how CCR2 modulates arthritis will have significant impact on potential therapeutic strategies to treat this chronic deblitating disease.
