Trafficking of monocytes and macrophages plays a critical role in atherosclerosis, resistance to intracellular pathogens, and antigen presentation, but the signals that regulate this trafficking are not well understood. The overall goal of this application is to elucidate the role of chemokine receptor 2 (CCR2), the receptor for the monocyte chemoattractant proteins (MCPs) in maintenance of atherosclerotic lesions, in resistance to intracellular pathogens, and in the development of type 1 (Thl) polarized immune responses. During the first two funding cycles of this grant we have cloned CCR2, and shown that CCR2 -/- mice develop less atherosclerosis than wild-type littermate controls. In the current application we will extend those findings, and will use newly created human CCR2 knock-in mice to test the hypothesis that CCR2 antagonists will regress atherosclerotic lesions. We will transplant segments of the aorta between wild-type and CCR2 -/- mice to provide a second, independent method for evaluating the role of CCR2 in lesion regression. Experiments in this application will utilize a novel system of conditional expression of reporter genes in transgenic mice to obtain kinetic information on macrophage efflux from simple to complex lesions. Work from our group and others has shown that CCR2-/- mice have a marked impairment in their ability to make interferon gamma, and this may contribute to their susceptibility to intracellular pathogens. We will use CCR2-/- and MCP-I -/- mice to elucidate the basis for this cytokine production defect. Recent results from our newly created MCP-5 -/- mice suggest a model in which MCP-1 attracts cells to the site of immunization/infection, and MCP-5 directs cells to the draining lymph node. We will extend those studies, and test the hypothesis that different members of the MCP-family of chemokines are preferentially expressed in different tissues. Completion of the specific aims of this grant will provide new data on the role of CCR2 in the maintenance and regression of atherosclerotic lesions, and in the trafficking of antigen presenting cells and the development of polarized T cell responses. This data will speak directly to the therapeutic prospects for CCR2 antagonists.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
J. David Gladstone Institutes
San Francisco
United States
Zip Code
Gonzalez, Julien; Mouttalib, Sofia; Delage, Christine et al. (2013) Dual effect of chemokine CCL7/MCP-3 in the development of renal tubulointerstitial fibrosis. Biochem Biophys Res Commun 438:257-63
Zouggari, Yasmine; Ait-Oufella, Hafid; Bonnin, Philippe et al. (2013) B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 19:1273-80
Charo, Israel F; Taub, Rebecca (2011) Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov 10:365-76
Saederup, Noah; Cardona, Astrid E; Croft, Kelsey et al. (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5:e13693
Yan, Wei; Si, Yue; Slaymaker, Sarah et al. (2010) Zmynd15 encodes a histone deacetylase-dependent transcriptional repressor essential for spermiogenesis and male fertility. J Biol Chem 285:31418-26
Daugherty, Alan; Rateri, Debra L; Charo, Israel F et al. (2010) Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE-/- mice. Clin Sci (Lond) 118:681-9
Si, Yue; Tsou, Chia-Lin; Croft, Kelsey et al. (2010) CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice. J Clin Invest 120:1192-203
Saederup, Noah; Chan, Liana; Lira, Sergio A et al. (2008) Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis. Circulation 117:1642-8
Jia, Ting; Serbina, Natalya V; Brandl, Katharina et al. (2008) Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J Immunol 180:6846-53
Tsou, Chia-Lin; Peters, Wendy; Si, Yue et al. (2007) Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest 117:902-9

Showing the most recent 10 out of 47 publications