Role of Chemokines in Regulating Oligodendrocyte Development, Astrogliosis and Demyelinating Disorders
Abstract
by
AMBER E. KERSTETTER-FOGLE
Oligodendrocyte development and maturation is crucial for efficient axonal transduction in the central nervous system. When perturbations in myelination occur such as with Multiple Sclerosis functional deficits rapidly follow. Previous studies demonstrated that local expression of CXCL1 in astrocytes of the spinal cord promotes oligodendrocyte proliferation and inhibits PDGF mediated migration by signaling through CXCR2 on oligodendrocyte precursor cells (OPCs). Inhibiting CXCL1/CXCR2 signaling in EAE and after lysolecithin injection, models of demyelination, promotes functional recovery, remyelination, and decreases in astrogliosis and microglial activation. CXCL1 treatment of astrocytes enhances secretion of proinflammatory cytokines and chondroitin sulfate proteoglycans that likely retard the process of repair. We hypothesis that decreasing CXCR2 signaling decreases immune cell infiltration, decreases astrogliosis and factors secreted downstream of the astrogliosis response, releasing OPCs from migratory arrest, enhancing endogenous OPC differentiation, leading to remyelination after injury. This enhancement in remyelination promotes functional recovery in EAE and increased MBP expression and myelin thickness consistent with remyelination. Thus the inhibition of CXCR2 enhances CNS repair suggestin this receptor is a therapeutic target for the treatment of demyelinating disorders, such as Multiple Sclerosis