Chemokines and their G-protein coupled receptors constitute a unique ligand-receptor system that governs leukocyte migration and effector function. Chemokines are present in most multicellular organisms, to mediate organ patterning during development. In mammals, chemokines also regulate the function of a sophisticated, flexible host-defense system. The central nervous system (CNS) lesions of multiple sclerosis (MS), an inflammatory demyelinating disease, contain specific populations of activated leukocytes, including monocytes, macrophages, microglia and lymphocytes. Understanding the molecular determinants of leukocyte trafficking to the CNS will promote progress towards effective treatment of MS. Data obtained in the previous round of funding supported our core hypothesis that individual chemokine/receptor pairs are selectively involved in the recruitment and activation of specific leukocyte populations in the CNS. Using experimental autoimmune encephalomyelitis (EAE) as a model system, we propose to examine our hypothesis in detail. We have carefully selected genetically-modified mice that will allow us to examine chemokine signaling in the critical cell populations implicated in EAE and MS. Using these powerful reagents, we intend to clarify how chemokines and their receptors govern the CNS recruitment and activation of diverse cell populations that take part in EAE: monocytes, lymphocytes, astrocytes, NK cells and microglia.
The Specific Aims address the following questions: 1. How do MCP- l/CCL2 and CCR2 govern cell recruitment and activation in the CNS? 2. How do fractalkine/CX3CL1 and CX3CR1 regulate the recruitment and activation of resident microglia and infiltrating cells in the CNS of mice with EAE? 3. How do CXCR3 and its ligands govern the accumulation and distribution of T-cells in the CNS of mice with EAE?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032151-13
Application #
7037568
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
1994-05-01
Project End
2009-02-14
Budget Start
2006-04-01
Budget End
2009-02-14
Support Year
13
Fiscal Year
2006
Total Cost
$354,836
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Katoh, Mitsuhiko; Wu, Bao; Nguyen, Huy Bang et al. (2017) Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation. Sci Rep 7:4942
Gyoneva, Stefka; Ransohoff, Richard M (2015) Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci 36:471-80
Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S et al. (2014) Ontogeny and functions of central nervous system macrophages. J Immunol 193:2615-21
Liu, Liping; Li, MeiZhang; Spangler, Lisa C et al. (2013) Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2. Genesis 51:587-95
Schafer, Dorothy P; Lehrman, Emily K; Kautzman, Amanda G et al. (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691-705
Veenstra, Mike; Ransohoff, Richard M (2012) Chemokine receptor CXCR2: physiology regulator and neuroinflammation controller? J Neuroimmunol 246:1-9
Mizutani, Makiko; Pino, Paula A; Saederup, Noah et al. (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 188:29-36
Engelhardt, Britta; Ransohoff, Richard M (2012) Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33:579-89
Kang, Zizhen; Liu, Liping; Spangler, Roo et al. (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284-92
Li, Meizhang; Hale, James S; Rich, Jeremy N et al. (2012) Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair. Trends Neurosci 35:619-28

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