169 Astrocyte and Oligodendrocyte Crosstalk prevent immune-mediated collateral damage130. These studies underscore the importance of the ECM in providing a healthy environment for remyelination. If disrupted, a remyelination promoting environment turns inhibitory, leading to impaired differentiation and proliferation of OPCs. Astrocytes are an important source of many ECM factors, and communicate with and influence OPCs and oligodendrocytes via secretion of ECM factors. In inflammatory CNS conditions infiltration of immune cells is a hallmark of disease and heavily dependent on the breakdown of the ECM. MMP2 and 9 are important in degradation of the lamina basalis, as well as infiltration of immune cells into the brain parenchyma. The activity of these proteins is regulated by tissue inhibitors of metalloproteinases (TIMPs). Although astrocytes express MMP2 and 9 both in vivo and in vitro, they also produce TIMP1123. Astrocytes promote oligodendrogenesis during and after injury through secretion of BDNF and TIMP-1154,155. This is also shown in TIMP-1 deficient mice that exhibit defective myelin repair23, indicating the importance of the ECM in remyelination. Another MMP that is active in remyelination is MMP7, which cleaves fibronectin aggregates present in demyelinating lesions in MS. These aggregates prevent OPC maturation and remyelination. Secreted proMMP7 is activated by astrocytic MMP3, indicating that astrocytes assist in this cleavage156. This shows that astrocytes are not only involved in the building of the ECM, but also in its breakdown and maintenance. In summary, astrocytic dysfunction results in a toxic extracellular environment with high levels of excitotoxicmolecules and pro-inflammatory cytokines such as IL-1β and TNF-α. On the other hand, their basal functions are essential in maintaining a healthy brain microenvironment where oligodendrocytes thrive and remyelinate the CNS. Although astrocytes can be detrimental in neurological disease they are also essential for the recovery from damage. Astrocytes are particularly important in early recovery by supporting oligodendrocyte migration and OPC differentiation. However, astrocytes become pathological in the chronic phase, exemplified by the glial scar formation in SCI or MS, in which hypertrophic astrocytes produce many factors that induce a harmful environment for mature oligodendrocytes and inhibit OPC differentiation44,130. Conclusion Astrocyte and oligodendrocyte interactions in healthy conditions and disease are complex and multifaceted. The widely considered view that astrocytes only react to damage in neurological diseases is changing to embrace the emerging evidence that these cells are essential to the development of the healthy CNS. On the other hand astrocytes are involved in the pathogenesis of several CNS diseases since loss of normal trophic functions of astrocytes results in damage to neurons and oligodendrocytes thereby exacerbating pathology. Furthermore, astrocytes are important for the regenerative capacities of the brain aiding oligodendrocyte proliferation, maturation and migration – a key step in repair in diseases such as MS and other demyelinating diseases. There is also a growing awareness that astrocytes and oligodendrocytes are not only targets for autoimmune responses in the context of neuroinflammation. Astrocytes play an important role as innate immune cells, e.g. by secreting chemokines, and as such influence other glia cells. Future studies into the communication between astrocytes and oligodendrocytes as well as their impact on other CNS cell types will provide new clues for controlling innate immunity and aiding repair in the CNS.
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