Convergence of sepsis-associated encephalopathy pathogenesis onto microglia

Abstract

Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, with symptoms ranging from mild delirium to deep coma. About 70% of patients with severe systemic infection develop SAE and with more than half of surviving patients suffering from long-term cognitive deficits, which seriously damaged the quality of their daily life and brought a heavy burden to society. The pathogenesis of SAE is multifactorial, including activated inflammation, blood- brain barrier (BBB) disruption, cerebral blood flow impairment, and neurotransmitter disturbances. Microglia mediate multiple SAE pathologies. In this review, we summarized the most recent findings in the roles of microglia in every stage of SAE pathogenesis, focusing on the molecular pathways in microglia activation and downstream effects. We also demonstrated the novel therapeutic studies targeting microglia in SAE. Deep insight into the role of microglia in SAE is of great importance in exploring pathogenesis and developing effective remedies of SAE.

Keywords: Glycometabolism; Lipid metabolism; Microglia activation; Neuroinflammation; Neurological dysfunction; Sepsis-associated encephalopathy (SAE).

Fig. 1

Pathogenesis of SAE. The pathogenesis of SAE is multifactorial, including blood-brain barrier disruption, neuroinflammation, cerebral ischemia, mitochondrial dysfunction, and neurotransmitter disruption. These factors involve in parallel and contribute to a varying degree to the development of SAE

Fig. 2

Pathways involved in microglia activation. Activation of microglia is related to multiple signaling pathways, including NF-κB, JAK-STAT, inflammasome, pyroptosis, et al. During sepsis, TLRs play a pivotal role in inducing the polarization of microglia toward M1 by activating NF-kB. SIRT1 and Foxc1 can induce anti-inflammatory responses by directly inhibiting NF-κB signaling. The expression of TRAM1, who is an adaptor of TLR4, is highly induced by LPS/ IFN-γ stimulation and significantly enhances M1 polarization of microglia. Sepsis induced activation of JAK/STAT3 signaling promotes the binding of STAT3 to the promoter of TERT and leads to increased TERT expression. The activation of NF-κB further induces the expression of NLRP3, Pro-IL-1β and Pro-IL-18, which are necessary for inflammasome activation. The activated NLRP3 inflammasome triggers self-cleavage and generates active caspase-1, which then cleaves pro-IL-1β and pro-IL-18, causing the release of the pro-inflammatory cytokines IL-1β/18. Caspase-1 also cleaves GSDMD into N-GSDMD, which causes the formation of pores in the cell membrane and triggers pyroptosis

Fig. 3

Glucose and lipid metabolism during microglia activation. Under neuroinflammatory conditions, microglia undergo metabolic reprogramming, especially in glucose and lipids metabolism, which is necessary for proper immune actions and cytokine release in the brain. Left: Microglia can recognize PAMPs (e.g., LPS) and other cellular inflammatory signals. Some inflammatory stimulus such as LPS and BAFF can cause increased glycolysis in microglia, promoting the expression of inflammatory genes, which are mainly through the activation of mTOR signal pathway. HIF-1α can enhance glycolysis through Akt/mTOR/HIF-1α pathway. The expression of Glut-1 was increased to uptake more glucose to meet the energy demand under inflammatory conditions. When inhibiting microglia glycolysis with glycolysis inhibitors 2-DG and 3-BPA, or by silencing GLUT1, NF-κB pathway is inhibited and thereby blocking the activation of microglia activation. Right: Microglia also recognize and phagocytose ApoE, myelin debris, lipoproteins, and other substances through certain receptors. Microglia recognize and phagocytose myelin debris through CD36 pathway. Myelin internalization increases CD36 expression through NRF2, skewing microglia to a less-inflammatory phenotype. While recognition of oxidized low-density lipoprotein (oxLDL) and amyloid-β by CD36 prime microglia for pro-inflammation phenotype by triggering the assembly of a heterotrimeric complex, which composed of CD36-TLR4-TLR6 and results in IL-1β transcription. ApoE bind to LRP1 and TREM2 on the microglial surface to inhibit microglial activation and reduce neuroinflammation. The phagocytosed lipid components can be hydrolyzed by PLA2 to release DHA and ARA. DHA and ARA can be oxidized to produce 4-HNE and 4-HHE, both of which can increase HO-1 expression and activate the NRF2 pathway, exerting anti-inflammatory effects

Fig. 4

Role of microglia activation in SAE. Microglial activation is strongly associated with the pathogenesis of SAE, especially in BBB disruption, neuroinflammation and neurotransmitter disruption. Under the systemic inflammatory condition, changes in BBB permeability occur, trigger the infiltration of peripheral immune cells into the brain parenchyma, as well as the entry of peripheral inflammatory factors, including cytokines, complements, NO, and chemokines. These inflammatory factors enter the brain and activate microglia. After activation, microglia perpetuate further inflammatory response by releasing inflammatory factors and inducing (by the release of TNF-α IL-1α, and C1q) the transformation of astrocytes into a neurotoxic subtype. Meanwhile, the secretion of neurotransmitters and the expression of their receptors in microglia are changed after microglia activation, leading to the disruption of neurotransmitter in the brain, such as glutamate accumulation. Microglia release large amounts of glutamate after activation. Increased glutamate release and impaired glutamate reuptake lead to extracellular glutamate accumulation and neurotoxicity. All of these pathogeneses induced by microglia ultimately result in neuronal death and cognitive impairment