Subsequent to demyelination in multiple sclerosis, myelin repair occurs but, as lesions age, the ability to remyelinate diminishes. Molecular pathways underlying oligodendrocyte behaviour during CNS remyelination remain to be elucidated. In this study, we report for the first time constitutive expression of the CXC/alpha chemokine receptors, CXCR1, CXCR2 and CXCR3, on oligodendrocytes in normal adult human CNS tissue, the levels of which were upregulated in multiple sclerosis and other neurological diseases (OND). In addition, both immature (A2B5+/O4+) and more mature (CNPase+) human oligodendrocytes in vitro expressed the same three receptors. The respective ligands to CXCR1, CXCR2 and CXCR3 [i.e. CXCL8/IL-8, CXCL1/GRO-alpha and CXCL10/IP-10), were absent in CNS tissue from normals and subjects with OND, but were present at high levels on hypertrophic (reactive) astrocytes at the edge of active (but not silent) multiple sclerosis lesions. Astrocytes in vitro could be induced to express chemokines following stimulation with pro-inflammatory cytokines. CXCL8 and CXCL1 production by human astrocytes at both the RNA and protein levels could be induced by interleukin (IL)-1beta, while CXCL10 was induced by both IL-1beta and interferon-gamma. Since these cytokines are integral to inflammatory events occurring at the margins of active multiple sclerosis lesions, their upregulation in these regions may underlie the dynamics of chemokine expression observed herein. The simultaneous expression of different CXC chemokine receptors on oligodendrocytes, and their ligands on astrocytes around multiple sclerosis lesions, may bespeak novel functional roles for these immune system molecules in the recruitment of oligodendrocytes and remyelination.

As part of a need to understand myelin repair mechanisms, molecular pathways underlying oligodendrocyte behavior and central nervous system (CNS) remyelination are currently key topics in multiple sclerosis (MS). In the present study, we report expression of a chemoattractant receptor of the immune system, the chemokine receptor, CXCR2, on normal and proliferating oligodendrocytes in active MS lesions. Proliferating oligodendrocytes were occasionally associated with reactive astrocytes positive for CXCL1 (GRO-alpha), the ligand for CXCR2. CXCL1 expression was not seen on astrocytes in control and normal CNS tissue, while CXCR2 expression was constitutive on oligodendrocytes. At the functional level, following stimulation with the proinflammatory cytokine, interleukin-1beta (IL-1beta), we found high-level synthesis of CXCL1 by human fetal astrocytes in vitro. In contrast, human oligodendrocytes in culture expressed the receptor, CXCR2, constitutively. We propose that the concurrence of CXCR2 on oligodendrocytes and induced CXCL1 on hypertrophic astrocytes in MS provides a novel mechanism for recruitment of oligodendrocytes to areas of damage, an essential prerequisite for lesion repair in this devastating human condition.

Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (ϳ150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity.

In rodents, the chemokine CXCL1 both induces the proliferation and inhibits the migration of oligodendrocyte precursor cells. We previously reported that in multiple sclerosis, the same chemokine is expressed by hypertrophic astrocytes, which associate with oligodendrocytes that express the receptor CXCR2. To investigate whether chemokines influence repair after autoimmune demyelination, we generated GFAP-rtTA ؋ ␤-Gal-TRE-CXCL1 double-transgenic (Tg) mice that inducibly overexpress CXCL1 under the control of the astrocyte-specific gene, glial fibrillary acidic protein. Experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, was induced in these animals (and controls) by the subcutaneous injection of myelin oligodendrocyte glycoprotein, and after disease onset, CXCL1 production was initiated by the intraperitoneal injection of doxycycline. Double-Tg animals displayed a milder course of disease compared with both single (CXCL1 or glial fibrillary acidic protein)-Tg and wild-type controls. Pathologies were similar in all groups during the acute stage of disease. During the chronic disease phase, both inflammation and demyelination were diminished in double-Tg mice and Wallerian degeneration was markedly decreased. Remyelination was strikingly more prominent in double-Tg mice, together with an apparent increased number of oligodendrocytes. Moreover, cell proliferation, indicated by BrdU incorporation within the central nervous system, was more widespread in the white matter of double-Tg animals. These findings suggest a neuroprotective role for CXCL1 during the course of autoimmune demyelination.

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