Dual Functions of Microglia in Ischemic Stroke

Abstract

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However, increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes, and endothelial cells within the brain parenchyma and the neurovascular unit.

Keywords: Inflammation; Ischemic stroke; Microglia; Signaling pathways.

Fig. 1

In ischemic stroke, resting microglia are activated and polarized into functionally distinct phenotypes that range between two extremes. Classical microglia produce pro-inflammatory mediators including tumor necrosis factor α (TNF-α), interleukin 1 beta (IL-1β), interferon-γ (IFNγ), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and proteolytic enzymes (MMP9, MMP3), identified as pro-inflammatory. Alternative microglia are characterized by the production of IL-10, transforming growth factor β (TGF-β), insulin-like growth factor (IGF1) and vascular endothelial growth factor (VEGF), which are pro-angiogenic and anti-inflammatory. Alternative microglia are associated with tissue repair and remodeling, immunity against parasites, and growth stimulation.

Fig. 2

Dynamic interactions between microglia and all cells within the neurovascular unit underlie the balance between acute injury and post-stroke recovery. After ischemic stroke, neuronal damage initiates an early activation processes of microglia. Activated microglia, in turn, have beneficial functions essential for neuron survival, and give rise to progressive neurotoxic consequences by the excess production of a large array of cytotoxic factors at the same time. Microglia are active earlier than astrocytes, which promote astrocyte activation. Astrocyte in turn further activate distant microglia and restrict microglial activity, with increasing secretion of characteristic inflammatory cytokines. In addition, microglial activation is an important course for damaging oligodendrocyte precursor cells/oligodendrocytes in ischemic white-matter injury. Disruption of the blood-brain barrier attracts and activates distant microglia, which in turn migrate towards the disrupted blood vessels and further start to phagocytize the damaged vessels. Activated microglia express pro-inflammatory cytokines extremely highly, which provokes the rapid disintegration of blood vessels, but also regulate primary brain endothelial cell proliferation and promote angiogenesis in a biphasic manner.