The Relationship of Astrocytes and Microglia with Different Stages of Ischemic Stroke

Abstract

Ischemic stroke is the predominant cause of severe morbidity and mortality worldwide. Post-stroke neuroinflammation has recently received increasing attention with the aim of providing a new effective treatment strategy for ischemic stroke. Microglia and astrocytes are major components of the innate immune system of the central nervous system. They can be involved in all phases of ischemic stroke, from the early stage, contributing to the first wave of neuronal cell death, to the late stage involving phagocytosis and repair. In the early stage of ischemic stroke, a vicious cycle exists between the activation of microglia and astrocytes (through astrocytic connexin 43 hemichannels), aggravating neuroinflammatory injury post-stroke. However, in the late stage of ischemic stroke, repeatedly activated microglia can induce the formation of glial scars by triggering reactive astrogliosis in the peri-infarct regions, which may limit the movement of activated microglia in reverse and restrict the diffusion of inflammation to healthy brain tissues, alleviating the neuroinflammatory injury poststroke. In this review, we elucidated the various roles of astrocytes and microglia and summarized their relationship with neuroinflammation. We also examined how astrocytes and microglia influence each other at different stages of ischemic stroke. Several potential therapeutic approaches targeting astrocytes and microglia in ischemic stroke have been reviewed. Understanding the details of astrocytemicroglia interaction processes will contribute to a better understanding of the mechanisms underlying ischemic stroke, contributing to the identification of new therapeutic interventions.

Keywords: Ischemic stroke; astrocyte-microglia interaction; astrocytes; microglia; neuroinflammation; stroke treatment.

Fig. (1)

The interaction between microglia and astrocyte in different stages of ischemic stroke. After the onset of ischemic stroke, microglia retract their processes and display an amoeboid shape as well as rapid polarization to two different subtypes with the stimulation of ATP and damage-associated molecular patterns released mainly by neurons: the pro-inflammatory phenotype, or the anti-inflammatory phenotype. In the early stage of post-stroke, pro-inflammatory microglia may destruct gap junctions and increase the permeability of astrocytic Cx43 hemichannels by releasing TNF-α and IL-1β. Conversely, astrocytes may activate microglia to the pro-inflammatory phenotype through releasing ATP and Glu by opened astrocytic Cx43 hemichannels, enhancing injury after ischemic stroke. While in the late stage of post-stroke, repeatedly activated pro-inflammatory microglia could trigger reactive astrogliosis via releasing TNF-α and IL-1β as well as inhibiting the expression of astrocytic Cx43, further forming glial scar in the peri-infract region together with reactive astrocytes. In turn, the glial scar could incorporate pro-inflammatory microglia, thus limiting the movement of activated pro-inflammatory microglia. As a result, the glial scar separates the ischemic core from healthy brain tissue and restricts the diffusion of inflammation. In addition, it remains to be clarified whether in the early or late post-stroke stage, anti-inflammatory microglia could both exert anti-inflammatory functions by producing IL-4, IL-10, IL-13, or TGF-β, as well as promote tissue repair and neurogenesis by producing IGF1, BDNF, and NGF.

Fig. (2)

Drugs targeting the activation and polarization of microglia. After the onset of ischemic stroke, microglia retract their processes and display an amoeboid shape as well as polarization to two different subtypes rapidly: the pro-inflammatory phenotype, or the anti-inflammatory phenotype. Pro-inflammatory microglia could release pro-inflammatory cytokines such as IL-6, IL-1β, IFN-ϒ, TNF-α, IL-15, IL-18, IL-23 [80, 81], aggravating the neuroinflammatory injury post-stroke. Anti-inflammatory microglia could release anti-inflammatory cytokines like IL-4, IL-10, IL-13, TGF-β [30] thereby attenuating the post-stroke neuroinflammatory injury. Different drugs are used as neuroprotective agents to treat ischemic stroke by acting on these events. Ginsenoside, protocatechuic acid, rapamycin, ABIN1 and electroacupuncture therapy can inhibit the microglial switch to pro-inflammatory phenotype, thus inhibiting the release of pro-inflammatory cytokines. Metformin, melatonin, L-3-n-Butylpthalide, and PACAP can promote the microglial switch to anti-inflammatory phenotype. In addition, minocycline can switch pro-inflammatory microglia to anti-inflammatory microglia, further promoting the release of anti-inflammatory cytokines.