163 Astrocyte and Oligodendrocyte Crosstalk by forming heterotypic gap junctions respectively Cx30:Cx32 and Cx43:Cx476,78. This physical contact is important in oligodendrocyte maturation and is often disrupted in demyelinating conditions. In EAE the reduction in Cx47 and Cx32 reduces oligodendrocyte-oligodendrocyte and astrocyte-oligodendrocyte interactions23. This reduction is also observed in active and chronic lesions in MS, neuromyelitis optica (NMO) and Baló’s disease79. Absence of Cx47 or Cx32 in oligodendrocytes exacerbates clinical EAE in mice associated with increased myelin loss but does not affect Cx30 andCx43 expression in astrocytes80. Pathogenicmutations inCx32 also contribute to Charcot-Marie-Tooth disease characterized by peripheral demyelination and neuropathy79. In contrast, Cx43 is upregulated in remyelinating MS lesions, emphasizing the importance of communication via gap junctions in remyelination79. The detrimental effect of Cx loss on remyelination may be attributed to the necessity of trophic support of oligodendrocytes by astrocytes, although whether the loss of Cx in gap junctions is the cause or consequence of myelin damage is unclear81. Astrocytes and oligodendrocytes play active roles in immune responses Emerging studies have changed the perception that astrocytes and oligodendrocytes are solely bystanders in inflammatory processes. In infectious and inflammatory CNS diseases oligodendrocytes have been reported to act as antigen presenting cells and produce immune molecules9 (Table 2). In neuroinflammation oligodendrocytes express many factors known to activate astrocytes82,83 (Figure 1). For example, in vitro astrocytes express receptors for e.g. CCL2 and CXCL10 which are mostly secreted to attract monocytes and macrophages84-87. In MS lesions oligodendrocyte and astrocyte expression of IL-17 suggests that glia, as well as T cells, promote the pro-inflammatory environment that attracts macrophages to the lesion88. In mice, administration of cuprizone, that damages and ablates oligodendrocytes, both oligodendrocytes and OPCs secrete IL-1β, a known pro-inflammatory cytokine89-91. CXCL1, CXCL2, CXCL3, CXCL5, and CXCL6 all bind the CXCR2 receptor, which is constitutively expressed on oligodendrocytes, but not present on astrocytes87,92. The CXCR2 receptor is upregulated in response to these cytokines that are secreted by oligodendrocytes, supporting autocrine regulation. Several CXCR2 ligands have previously been associated with OPC proliferation and differentiation93, indicating that oligodendrocytes regulate their own proliferation. Granulocyte macrophage colony stimulating factor (GM-CSF) is upregulated in resting oligodendrocytes92 which has been found to be anti-apoptotic for neurons and neuroprotective in models of stroke. Additionally, astrocytes secrete CXCL1 in spinal cord injury and in MS lesions, both in vivo and in vitro, which may act to recruit oligodendrocytes87,94. Gap junctions are also reported to play an immunoregulatory role for example Cx43 loss in astrocytes increases recruitment of immune cells in the brain as well as inducing an atypical reactive astrocyte phenotype that secretes both pro- and anti-inflammatory factors81,117,118.
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