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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052755-03
Application #
7480344
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2006-09-19
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$305,648
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Martinez, H G; Quinones, M P; Jimenez, F et al. (2011) Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome. Diabetologia 54:2660-8
Chiao, Ying Ann; Dai, Qiuxia; Zhang, Jianhua et al. (2011) Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. Circ Cardiovasc Genet 4:455-62
Zamilpa, Rogelio; Kanakia, Rushit; Cigarroa 4th, Joaquin et al. (2011) CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 300:H1418-26
Ibarra, Jessica M; Quinones, Marlon P; Estrada, Carlos A et al. (2011) CD8?? dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice. Immunobiology 216:971-8
Jimenez, Fabio; Quinones, Marlon P; Martinez, Hernan G et al. (2010) CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B. J Immunol 184:5571-81
Martinez, Hernan G; Prajapati, Suresh I; Estrada, Carlos A et al. (2009) Images in cardiovascular medicine: Microscopic computed tomography-based virtual histology for visualization and morphometry of atherosclerosis in diabetic apolipoprotein e mutant mice. Circulation 120:821-2
Quinones, Marlon P; Kalkonde, Yogeshwar; Estrada, Carlos A et al. (2008) Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-kappaB and Akt. Mol Cell Neurosci 37:96-109
Quinones, Marlon P; Martinez, Hernan G; Jimenez, Fabio et al. (2007) CC chemokine receptor 5 influences late-stage atherosclerosis. Atherosclerosis 195:e92-103
Ahuja, Seema S; Estrada, Carlos A; Lindsey, Merry L (2007) Crosstalk between cytotoxic T-lymphocyte associated antigen-4 and interleukin-12 in cytotoxic T-lymphocyte-mediated myocarditis: adding another link to the chain. Circ Res 101:218-20