CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis

Abstract

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.