Astrocytes and Microglia: In Sickness and in Health

Abstract

Healthy central nervous system (CNS) development and function require an intricate and balanced bidirectional communication between neurons and glia cells. In this review, we discuss the complementary roles of astrocytes and microglia in building the brain, including in the formation and refinement of synapses. We discuss recent evidence demonstrating how these interactions are coordinated in the transition from healthy physiology towards disease and discuss known and potential molecular mechanisms that mediate this cellular crosstalk.

Keywords: astrocytes; brain development; microglia; neuroimmune; synapses.

Figure 1:. Function of the astrocyte-microglia module from homeostasis to pathology.

Under physiologic conditions astrocytes (ochre) and microglia (blue) support neuronal functions, whereas in pathology they lose some of their supportive functions in favor of optimizing survival. This is accompanied by a change in morphology, secretome and increase in reactive markers and phagocytic activity.

Figure 2:. Mechanisms for regulating the astrocyte-microglia module.

Astrocytes (ochre) and microglia (blue) can inter-signal (factors A and B) and thereby amplify or diminish their individual or shared responses (communication). This signaling can be adjusted by ligands (factor C) that target both cell types (synchrony) or that target one cell type that indirectly alters (factor D) the other cell type (relay effects).

Figure 3:. Molecules involved in astrocyte-microglia communication.

Examples of the types of shared signaling pathways described in Figure 2 are shown here. Molecules that induce synchronous responses in both astrocytes and microglia via distinct receptors include norepinephrine and purines. More complex interactions involving intermediary cells have also been described- for example, astrocyte-derived TGF-beta leads to neuronal release of complement, which acts on microglia. Astrocytes and microglia can directly impact one another via molecules like IL1a, TNF, and IL-33. Finally, blood derived signals, such as circulating bacterial metabolites and likely others can act on both astrocytes and microglia through shared receptors. Again, intermediate cell types can be relevant, for example astrocyte-derived IL-1 could alter permeability of the blood brain barrier, thereby enabling microglial activation.