The functional role of these alternate receptors is currently unknown

The functional role of these alternate receptors is currently unknown. of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus provide a therapeutic target for demyelinating diseases. Keywords: oligodendrocyte, myelin repair, spinal cord, Multiple Sclerosis, remyelination, neuroinflammation INTRODUCTION Multiple sclerosis (MS) is a devastating heterogeneous inflammatory demyelinating disorder of the central nervous system (CNS) affecting young adults (Davis, DIPQUO 1970; Antel, 1999; Compston and Coles, 2002; Benedict and Bobholz, 2007). Hallmarks of the disease include recurrent demyelinating episodes that result in the progression of neurological deficits due to the slowing and ultimately failure of axonal conduction (Davis, 1970; Waxman, 1977; Blakemore et al., 2000; Baumann and Pham-Dinh, 2001; Nashmi and Fehlings, 2001; Bjartmar et al., 2003). Remyelination frequently occurs during early stages of disease, however this fails during later disease stages and the number of persistent demyelinating lesions increases (Chari, 2007). The majority of current therapies for MS target the inflammatory response that is distinctive of DIPQUO the disease (Miller et al., 1998; Hohol et al., 1999; Miller et al., 1999; McFarland and Martin, 2007; Trapp and Nave, 2008). Although active inflammation predominates in the initial stages of the disease, the neurological disabilities associated with the chronic disease accumulates independent of inflammatory mediators (McFarland and Martin, 2007; Frohman et al., 2008) and long-term recovery requires myelin repair. Models of MS include the experimental autoimmune encephalomyelitis (EAE) (Cross et al., 1991), where widespread demyelination is largely a consequence of immunological attack on resident CNS myelin following immunization by specific myelin peptides. Focal demyelinated lesions can be induced by direct injection of lysolecithin (LPC) (Ousman and David, 2000; Bambakidis et al., 2003; Mi et al., 2005) where demyelination is largely a consequence of chemical dissolution of myelin sheaths. Finally, cuprizone intoxication (Zatta et al., 2005) results in demyelination largely as a consequence of metabolic perturbations. In the present study, we utilize lysolecithin lesions and MOG35-55 peptide induced EAE to assess the efficacy of inhibiting the CXCR2 chemokine receptor in mediating demyelination and remyelination. Chemokines, or chemoattractant cytokines, comprise a family of inducible secreted molecules of small molecular weight (8-10kDa) (Hesselgesser and Horuk, 1999; Fernandez and Lolis, 2002; Laing and Secombes, 2004), that function as activators of leukocytes, wound healing, modulators of angiogenesis, and tumorigenesis (Robinson et al., 2001; Smith et al., 2005; Charo and Ransohoff, 2006). The functions of chemokines have been primarily implicated in modulation of immune coordination and inflammation (Fernandez and Lolis, 2002; Flynn et al., 2003; Laing and Secombes, 2004; Charo and Ransohoff, 2006) where they contribute to the localization of specific cells with fine spatio-temporal precision (Charo and Ransohoff, 2006). Chemokine receptors are G-protein coupled receptors (GPCRs) usually linked to pertussis toxin sensitive Gi proteins (Bajetto et al., 2001). The receptor CXCR2 is the primary mediator of signaling by the chemokine CXCL1 (Katancik et al., 2000), a soluble secreted chemoattractive molecule of the ELR family of CXC chemokines. Their interaction initiates intracellular processes that modulate a number of cellular events, including migration, proliferation, and differentiation (Bajetto et al., 2001; Miller, 2002; Tsai et al., 2002). Several studies have characterized the expression and function of chemokine receptors on neural cells in the vertebrate CNS. For example, the CXCR4 receptor and its cognate ligand SDF1 have been implicated in the control of neuronal precursors in the hippocampus and cortex (Imitola et al., 2004). During oligodendrocyte development, signaling through CXCR2 in DIPQUO combination with platelet derived growth factor AA promotes oligodendrocyte precursor proliferation (Robinson et al., 1998; Robinson et al., 2001; Woodruff et al., 2004). Furthermore, the CXCR2 signaling pathway contributes to the correct localization of oligodendrocytes in white matter tracts of the spinal cord (Miller, 2002; Tsai et al., 2002; Padovani-Claudio et al., 2006). Elevated levels of CXC chemokine expression are associated with a range of pathological CNS insults including infection, tumors, ischemia and demyelination (Liu et al., 1993; Spanaus et al., 1997; Filipovic et al., DIPQUO 2003; Keane et al., 2004; Sue et al., 2004; Omari et al., 2006; Valles et al., 2006) DIPQUO and this may reflect ingress of immune cells in response to local expression. For example, overexpression of CXCL1 in oligodendrocytes induces neutrophil invasion and astrogliosis (Tani et al., 1996; Tanabe Rabbit Polyclonal to Shc (phospho-Tyr427) et al., 1997). Overexpression of.