Resistance to Experimental Autoimmune Encephalomyelitis in Mice Lacking the Cc Chemokine Receptor (Ccr2)

By L. Izikson, R. Klein, I. Charo, Howard L. Weiner, A. Luster. Journal of Experimental Medicine, 2000

641 citations recorded by the source corpus.

Monocyte recruitment to the central nervous system (CNS) is a necessary step in the development of pathologic inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Monocyte chemoattractant protein (MCP)-1, a potent agonist for directed monocyte migration, has been implicated in the pathogenesis of EAE. Here we report that deficiency in CC chemokine receptor (CCR)2, the receptor for MCP-1, confers resistance to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide 35–55 (MOGp35–55). CCR2−/− mice immunized with MOGp35–55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well the chemokine receptors CCR1, CCR2, and CCR5. Additionally, T cells from CCR2−/− immunized mice showed decreased antigen-induced proliferation and production of IFN-γ compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. These data indicate that CCR2 plays a necessary and nonredundant role in the pathogenesis of EAE.

View Paper: https://www.semanticscholar.org/paper/28144f2ef421b4a62fd1f2282ad5c63602761b59

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

1. R. Ransohoff
2. A. Luster
3. O. Butovsky
4. S. Hickman
5. Yuanshu Dong
6. I. Charo
7. C. D’Mello
8. R. Yamasaki

Citations in the corpus

• Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. (2007, unknown): “Mice that are genetically deficient in CCR2 (CCR2 –/– mice) exhibit markedly reduced tissue recruitment of monocytes in peritonitis (4), auto-immune encephalitis (5), tuberculosis (6), and atherosclerosis (7).”
• Immune function of astrocytes (2001, background): “Mice deficient in CCR2 are resistant to EAE (Fife et al., 2000; Izikson et al., 2000), as are MCP-1-deficient mice (Huang et al., 2001), indicating the importance of MCP-1 and its receptor in the disease of EAE.”
• Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis (2001, background): “In recent definitive studies of EAE using CCR2-deficient mice (37, 38), the relevant ligand for the deleted receptor was not defined.”
• Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool (2011, background): “Similarly, blockade or genetic deletion of CCR2, a chemokine receptor that is known to be involved in monocyte and T cell trafficking, prevents severe disease and can lead to faster remissio”
• International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors (2014, unknown): “On the other hand, recombinant smCKBP did not alter disease in EAE or collageninduced arthritis models.”
• Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease (2007, background): “Ccr2 is involved in mononuclear phagocyte infiltration of the brain in a mouse model for multiple sclerosi”
• Chemokines and disease (2001, background): “In contrast, two groups have shown that CCR2-deficient mice are almost completely protected from MOG-induced disease, despite some discrepancies between the two sets of dat”
• Three or more routes for leukocyte migration into the central nervous system (2003, result): “Mice that lacked either CCR2 or one of its ligands, CCL2, were relatively resistant to the development of EAE, despite having T-cell responses that were equivalent to those observed in wild-type mic”
• Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation (2009, background): “Despite the redundancy in the chemokine system, others have also identified the MCP-1/CCL2CCR2 axis as being vital in driving cerebral monocyte infiltration in models of CNS inflammatory pathologies, including experimental autoimmune encephalitis (Izikson et al., 2000; Huang et al., 2001) and human ”
• Differential roles of microglia and monocytes in the inflamed central nervous system (2014, background): “CCR2 is essential for monocyte recruitment to CNS tissues during immune-mediated inflammation (Fife et al., 2000; Izikson et al., 2000; Savarin et al., 2010).”
• Chemokines as regulators of T cell differentiation (2001, background): “In contrast, CCR2 −/− mice have markedly reduced T cell IFN-γ responses in lymph nodes that drain the antigen exposure sites, diminished type 1 granuloma responses, defects in clearance of intracellular pathogens and increased resistance to the T H 1-mediated disease, experimental autoimmune enceph”