Glial Cells: Role of the Immune Response in Ischemic Stroke

Abstract

Ischemic stroke, which accounts for 75-80% of all strokes, is the predominant cause of morbidity and mortality worldwide. The post-stroke immune response has recently emerged as a new breakthrough target in the treatment strategy for ischemic stroke. Glial cells, including microglia, astrocytes, and oligodendrocytes, are the primary components of the peri-infarct environment in the central nervous system (CNS) and have been implicated in post-stroke immune regulation. However, increasing evidence suggests that glial cells exert beneficial and detrimental effects during ischemic stroke. Microglia, which survey CNS homeostasis and regulate innate immune responses, are rapidly activated after ischemic stroke. Activated microglia release inflammatory cytokines that induce neuronal tissue injury. By contrast, anti-inflammatory cytokines and neurotrophic factors secreted by alternatively activated microglia are beneficial for recovery after ischemic stroke. Astrocyte activation and reactive gliosis in ischemic stroke contribute to limiting brain injury and re-establishing CNS homeostasis. However, glial scarring hinders neuronal reconnection and extension. Neuroinflammation affects the demyelination and remyelination of oligodendrocytes. Myelin-associated antigens released from oligodendrocytes activate peripheral T cells, thereby resulting in the autoimmune response. Oligodendrocyte precursor cells, which can differentiate into oligodendrocytes, follow an ischemic stroke and may result in functional recovery. Herein, we discuss the mechanisms of post-stroke immune regulation mediated by glial cells and the interaction between glial cells and neurons. In addition, we describe the potential roles of various glial cells at different stages of ischemic stroke and discuss future intervention targets.

Keywords: astrocytes; ischemic stroke; microglia; neuroinflammation; oligodendrocytes.

Figure 1

Possible crosstalk between glial cells in ischemic stroke. (1) Microglial activation is an important process in inflammatory response after ischemic brain injury. The release of cellular contents and debris from dead cells, such as other glial cells and neurons, can cause microglial activation. These fragments will also be engulfed by microglia. (2) The M1 and M2 microglia have significantly different biological functions. In short, M1 microglia have a stronger proinflammatory phenotype, whereas M2 microglia are anti-inflammatory and have a robust function in phagocytosis. M1 and M2 microglia described in this paper are the two most widely studied types. Other types of microglia and their biological function need to be further explored. (3) Activated microglia induce the activation of astrocytes by releasing cytokines such as IL1α, TNFα, and C1q. (4) Astrocytes have a regulatory effect on microglia by releasing cytokines such as IL-33. (5) Activated microglia and astrocytes can damage neurons. (6) Astrocytes may have neuroprotective functions by producing several types of neurotrophic factors. (7) Activated astrocytes have damaging effects on oligodendrocytes. (8) Microglia may have a dual role in the regulation of oligodendrocytes: inflammatory factors produced by activated microglia cause impairment of oligodendrocyte/OPCs, whereas VEGF-C produced by microglia stimulates OPC proliferation and M2 microglia can drive oligodendrocyte differentiation during remyelination.