Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

Abstract

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.

Keywords: cognitive impairment; inflammatory factors; microglia; sepsis; sepsis-associated encephalopathy (SAE).

Figure 1

Proinflammatory cytokines, such as IL-1α, IL-1β, IL-1, and HMGB1, pass through the BBB through different receptors and activate microglia, which further damage the BBB by releasing inflammatory factors, causing an inflammatory cascade. At the same time, microglia release ROS and NO, causing damage and even apoptosis of neurons in the brain.

Figure 2

Microglia perform functions in the central nervous system.

Figure 3

Most microglia can be divided into two opposite types: classical (M1) or alternative (M2). M1 microglia release inflammatory mediators, such as IL-6 and CCL2, which induce inflammation and neurotoxicity. M2 microglia release anti-inflammatory mediators, such as IL-10 and neurotrophic factor, which induce anti-inflammatory and neuroprotective effects.