The glia-immune network: Astrocytes and oligodendrocytes as microglial co-ordinators in health and disease

It has long been established that microglia are integral to the CNS immune system. Their surveying and adaptive nature is key in brain development and maintaining homeostasis as well as in the manifestation and progression of neuropathology. However with advancing technology it is becoming increasingly recognised that they do not serve this role in isolation. Previously most work has focused on microglia-derived signalling, with less attention on the sensing and signalling capacity of macroglia (astrocytes, oligodendrocytes). Recent developments in single-cell transcriptomics have allowed extensive analysis of cell profiles in health and disease; these studies have drawn attention to the capacity of macroglia to also engage in immune signalling pathways. This is particularly relevant in neuropathologies, including in Alzheimer's disease (AD), where specific disease-associated profiles of glia (DAGs) have been established. These changes are predominantly related to immune pathways, which were long considered limited to immune cells, including cytokine and chemokine production, antigen presentation and phagocytosis. There is an increasing body of evidence that glia should be considered as active components of the CNS immune system forming a glia-specific immune-like network, whereby macroglia, acting as sensors of the CNS microenvironment, function within this network to co-ordinate diverse CNS effect(s)/function(s). To gain an in-depth understanding of AD pathology, the intimate molecular dialogue of glia needs to be elucidated. This review aims to examine the evidence for macroglia-derived immune signalling and its relevance in health and disease.