The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation

Abstract

Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.

Keywords: Blood–brain barrier; Cognitive impairment; Mitochondrial dysfunction; Sepsis-associated encephalopathy; Synaptic dysfunction.

Fig. 1

Routes of cytokines enter the brain. Route I: The systemic inflammatory response induced by sepsis causes extensive cerebral vascular endothelial cell inflammatory response, which may be responsible for the destruction of the BBB. This route is known as the humoral route or humoral mechanism. Peripheral immune cells and cytokines enter the brain parenchyma through the leaked BBB. Route II: Peripheral infiltrating immune cells exacerbate BBB damage. Microglia are activated to release cytokines and adhesion molecules, which cooperate with infiltrating cells to further aggravate BBB damage. This is known as the cellular route. Route III: The leakage of BBB results in the entry of cytokines into the brain parenchyma, where they are subsequently recognized by cytokine receptors expressed on neurons and glial cells in the limbic system, brain stem, and hypothalamic-pituitary system. Cytokine receptors on afferent nerve fibers and transmit cytokine signals to the brain. This process is facilitated and assisted by CNS resident inflammatory cells. Abbreviations: BBB, blood–brain barrier; CXCL-1/2/3, chemokine (C-X-C motif) ligand 1/2/3 protein; CCL-2, chemokine (C–C Motif) ligand 2; DAMP, damage-associated molecular pattern; EC, endothelial cell; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; TNF-α: tumor necrosis factor α

Fig. 2

Phenotypic diversity of context-dependent microglia in the brain under conditions of inflammation mimicking sepsis after LPS challenge. Depending on the stage of disease progression, microglia acquire distinct heterogeneous phenotypes. They have unique molecular expression patterns and are defined as DAM. Through mimicking systemic inflammatory and septic environment using LPS to stimulate primary microglia in vitro, heterogeneous microglia defined by specific genetic signatures is identified by RNA-sequencing analysis at different times after LPS challenge. Microglial gene expression was analyzed by RNA sequencing (single-cell RNA-sequencing, global RNA-sequencing). Key transcriptional profiles of microglia at each phase are shown [53, 54]. Abbreviations: DAM, disease-associated microglia; LPS, lipopolysaccharides; RNA-seq, RNA-sequencing

Fig. 3

Mechanisms of neuronal mitochondrial dysfunction and brain dysfunction in SAE. Neurons hyperexcited by recognizing DAMPs, followed by the attack of activated microglia and inflammatory cytokines, functional disorder and metabolic disturbances emerge. Due to the extensive and systemic inflammatory response, cells receive insufficient oxygen and are unable to meet their metabolic needs, which leads to  an excessive generation of ROS and RNS. Neuronal mitochondrial dysfunction occurs immediately. The basis of abnormal mitochondrial function in neurons is characterized by increased mitochondrial inner membrane aperture, reduced ATP synthesis, and impaired respiratory chain. The subsequent disturbance of energy supply in neurons and the release of mitochondrial cytochrome c activate neuronal apoptosis cascade. Decreased antioxidant enzymes and increased mitochondrial ROS are lethal to neurons. This could disrupt the process of synaptic transmission (neurotransmission) and synaptic activity. At the same time, DAMPs are recognized by microglia, activating to secrete pro-inflammatory cytokines (e.g., iNOS, TNFα, IL-6) to facilitate neuroinflammation and accelerate brain damage. Abbreviations: ACH, acetylcholine; ATP, adenosine triphosphate; IL, interleukin; RNS, reactive nitrogen species; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle; TNF-α: tumor necrosis factor α