The current application focuses on CXCR2, a chemokine receptor present both on leukocytes and parenchymal central nervous system (CNS) cells. Our preliminary findings and recent reports demonstrate that CXCR2 on circulating leukocytes is decisive with regard to the outcome of EAE or cuprizone-mediated demyelination. Our recent findings show further that CXCR2 on CNS cells also regulates myelin repair. CXCR2 is the first chemokine receptor which promotes myelin destruction and hinders myelin repair. Our studies will address the fundamental role of CXCR2 in demyelination and remyelination, by performance of the following Specific Aims:
Aim 1. We will define the pathways by CXCR2 expression by leukocytes contributes to cuprizone- mediated demyelination. Hypothesis: CXCR2 promotes demyelination through recruitment of monocytes to cuprizone lesions. The vast majority of hematogenous inflammatory cells in cuprizone lesions are monocyte- derived macrophages, leading us to suggest that CXCR2 acts through macrophage recruitment. The results of our proposed experiments will define how myeloid-cell CXCR2 contributes to this process.
Aim 2. We will use an in-vitro model of demyelination-remyelination to address how the presence of CXCR2 impairs remyelination. Preliminary results showed that antibody-mediated blockade or genetic absence of CXCR2 led to accelerated remyelination of brain slices in-vitro. Hypothesis: The presence of CXCR2 on oligodendrocyte progenitor cells impairs their proliferation and differentiation in demyelinated lesions. This in-vitro model recapitulates remyelination in-vivo, particularly those aspects which take place within the demyelinated lesion. This convenient, manipulable model will be used to examine the cellular and molecular basis by which CXCR2 hinders remyelination.
Aim 3. We will define CNS cells whose expression of CXCR2 leads to inefficient remyelination. To address CXCR2 function in the CNS, we generated a conditional CXCR2 allele. Hypothesis: CXCR2 impairs remyelination by slowing accumulation of oligodendrocyte progenitors in lesions and hindering their proliferation and differentiation. Mice harboring a conditional CXCR2 allele will be crossed with available mice expressing cre-ER(T2) in individual cell types, allowing efficient lineage-specific, inducible deletion. We will analyze cuprizone-mediated demyelination and remyelination to probe how CXCR2 expression in CNS cells regulates this process. These studies will provide essential data for designing clinical trials of CXCR2 blockade in MS.
This grant focuses on CXCR2, a cellular receptor present both on inflammatory white blood cells and brain cells. CXCR2 both promotes myelin destruction and hinders myelin repair. Our studies will address the fundamental role of CXCR2 in demyelination and remyelination, by using novel models including in-vitro brain slices and genetically modified mice, allowing the receptor to be removed either from inflammatory white blood cells or from CNS cells. Ongoing clinical trials for pulmonary disease use drugs that block CXCR2 and our studies will provide essential data for designing clinical trials of CXCR2 blockade in MS.
|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|
|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|
|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|
Showing the most recent 10 out of 84 publications