164 Chapter 7 OPC Oligodendrocyte Astrocyte Stressed oligodendrocyte GM-CSF CCL2 CXCL10 IL-1β IL-17 CCL2 IL-1β Figure 1. Oligodendrocytes secrete factors that impact on astrocytes. Stressed oligodendrocytes release factors that have beneficial effects (green) on astrocytes such as CCL2 to reduce inflammation. In contrast detrimental factors (red) such as IL-1β exacerbates inflammation. Healthy oligodendrocytes and OPCs also interact with astrocytes by secretion of GM-CSF and CCL2 as well as IL-1β. Many immune factors are secreted by both oligodendrocytes and astrocytes in vitro i.e. IL-1β, CXCL10 and IL17, underscoring a possible immune function of these cells89. In addition, astrocytes also secrete tumour necrosis factor-α (TNF-α), IL-1β, interferon-γ (IFN-γ), fibroblast growth factor-2 (FGF-2), PDGF, and BMPs, factors known to influence oligodendrocytes and OPCs3,119 (Figure 2, Table 2). TNF-α is recognized by TNFR1 and induces pro-inflammatory effects, while binding to TNF-αR2 induces anti-inflammatory effects. Both TNFR1 and TNFR2 are expressed on oligodendrocytes9, and both are upregulated during inflammation8 indicating that oligodendrocytes could trigger both pro- and antiinflammatory responses. Likewise, astrocytes express predominantly TNFR1 but are capable of upregulating TNFR2 after stimulation by TNF-α3,120, suggesting an autocrine feedback loop. While inhibition of TNF-α is an effective therapy in autoimmune diseases such as rheumatoid arthritis, this approach has been less straightforward in MS121, recent data shows that selective modulation of TNFRs by activating TNFR2 and/or silencing TNFR1 might have therapeutic potential122. IL-1β is expressed by astrocytes during ischemic stroke, as well as neuroinflammatory disease although the precise mechanisms of IL-1β remain unclear100,123. IL-1β was also found in active MS lesions in reactive astrocytes and in preactive lesions where it might act on oligodendrocytes and astrocytes in lesion formation124. IFN-γ has both pro- and anti-inflammatory effects, as treatment with IFN-γ exacerbates MS pathology, but also induces neurotrophic factor production in astrocytes, which are also able to produce IFN-γ104,107. FGF-2 is secreted by astrocytes after focal demyelination in mice, and has been shown to promote OPC proliferation yet inhibit their differentiation to oligodendrocytes4,24. BMPs are upregulated in EAE, and direct OPC differentiation into the astrocyte lineage24. Lastly, insulin-like growth factor-1 (IGF-1) also induces OPC maturation109.
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