Interaction of Microglia and Astrocytes in the Neurovascular Unit

Abstract

The interaction between microglia and astrocytes significantly influences neuroinflammation. Microglia/astrocytes, part of the neurovascular unit (NVU), are activated by various brain insults. The local extracellular and intracellular signals determine their characteristics and switch of phenotypes. Microglia and astrocytes are activated into two polarization states: the pro-inflammatory phenotype (M1 and A1) and the anti-inflammatory phenotype (M2 and A2). During neuroinflammation, induced by stroke or lipopolysaccharides, microglia are more sensitive to pathogens, or damage; they are thus initially activated into the M1 phenotype and produce common inflammatory signals such as IL-1 and TNF-α to trigger reactive astrocytes into the A1 phenotype. These inflammatory signals can be amplified not only by the self-feedback loop of microglial activation but also by the unique anatomy structure of astrocytes. As the pathology further progresses, resulting in local environmental changes, M1-like microglia switch to the M2 phenotype, and M2 crosstalk with A2. While astrocytes communicate simultaneously with neurons and blood vessels to maintain the function of neurons and the blood-brain barrier (BBB), their subtle changes may be identified and responded by astrocytes, and possibly transferred to microglia. Although both microglia and astrocytes have different functional characteristics, they can achieve immune "optimization" through their mutual communication and cooperation in the NVU and build a cascaded immune network of amplification.

Keywords: LPS; NVU; astrocyte; microglia; neuroinflammation; stroke.

Figure 1

Illustration of microglia and astrocytes in NVU. In the context of the NVU, astrocytes are located in the center between neurons and endothelial cells (ECs). Astrocytes are closely associated with neurons and blood vessels as versatile cells. Astrocytes communicate with neuronal pre- and postsynaptic terminals to help modulate synaptic transmission. It has been reported that one astrocyte can supervise over 100,000 synapses. Astrocytes extend end-feet processes to cover the surface of cerebral blood vessels with a ratio of ~99% to modulate CBF or the BBB. Astrocytes can be organized into syncytial structures of up to 100 units by gap junctions to facilitate long-range signaling. Microglia account for about 5–15% of all cells in the human brain. Under physiological or pathological conditions, they scan their environment through scavenging functions. Microglia firstly react to brain insults like “pioneers,” monitoring and transmitting “danger.” Astrocytes with dominant quantity may be “reserve forces” and amplify the neuroinflammation, owing to their syncytium of the structure, and function, and strategic position to mobilize peripheral immunity.

Figure 2

Illustration of microglia, astrocytes, and neuroinflammation. Microglia are more sensitive to pathogens/damage such as LPS or stroke, firstly activated into M1-like phenotypes via PAMP/DAMP and promote the secretion of inflammatory factors such as TNF-a, IL-1, etc. to trigger reactive astrocyte (A1). As the insult limited and the NVU is remodeling, the local environmental factors change and determine M2-like phenotype to upregulate microglial phagocytosis and secretion of IL10, TGF, etc. Simultaneously, the local environmental factors may promote the switch to A2. Astrocytes communicate simultaneously with both neurons and blood vessels as versatile cells to maintain the function of neurons and the blood–brain barrier, and their subtle changes may be captured and responded by astrocytes and even transferred to microglia. A variety of molecular signals such as ATP, endothelin, etc. trigger reactive astrocytes (A1) and A1 upregulates many genes of the classic complement cascade such as C1r, C1s, C3, and C4, which communicate with microglia via some corresponding complement receptors; A2 elevates the levels of neurotrophic factors and cytokines such as CLCF1, LIF, IL-6, IL-10, and thrombospondins to promote neuronal survival and repair; the local environmental factors promote the switch to M2-like phenotype.

Figure 3

The communications of microglia and astrocytes. Pathogens/damage trigger M1-like microglia via TLR4. During the neuroinflammation induced by LPS or stroke, Microglia are more sensitive to pathogens/damage, firstly activated, and secrete the common “molecular signals,” such as IL-1 and TNF-a, to trigger reactive astrocytes. Different types of insults release different combinations of these molecules, which in turn trigger different responses. It has been demonstrated that inflammation factors induced by LPS, such as TNF-α, IL-1a, and C1a, can trigger reactive astrocytes. In stroke, however, the inflammatory factors secreted by activated microglia(M1), such as TNF-α, IL-1β, and IL-6, are significantly elevated. Recombinant human HMGB1 (rhHMGB1) can trigger microglial activation via the TLR4 and increase production of TNF-α, which in turn stimulates microglia to release large amounts of HMGB1 to active more microglia. There seems to be self-feedback loop in the activation process of microglia.