Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

Abstract

Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.

Keywords: brain; inflammasome; microglia; neuroinflammation; neurotoxicity; oxidative stress; sepsis-associated encephalopathy; synaptic dysfunction.

Figure 1

Overview of the pathophysiology of sepsis-associated encephalopathy. DAMPs (damage-associated molecular patterns), PAMPs (pathogen-associated molecular patterns), PRR (pattern recognition receptors), TNF (tumor necrosis factor), IL-1, IL-6 (interleukins 1 and 6), iNOS (inducible nitric oxide synthase), COX2 (cyclooxygenase 2), PGs (prostaglandins), ROS (reactive oxygen species), CNS (central nervous system), OXPHOS (oxidative phosphorylation), DIC (disseminated intravascular coagulation).

Figure 2

Molecular mechanisms of microglia activation in sepsis-associated encephalopathy. Classically (M1) activated microglia express Toll-like receptors (TLR) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and trigger NF-κB-dependent pro-inflammatory gene expression, upregulating inflammatory cytokines such as IL-6, IL-12, TNF-α, and IL-23 and components of the inflammasome pathway. IL-23 mediates inflammatory response by inducing IL-17 production and the secretion of pro-inflammatory cytokines. Inducible NOS is upregulated in M1 microglia, and NO induces a metabolic shift to glycolysis through mitochondrial inhibition. Inflammation and hypoxia activate the mTOR/ HIF-1α pathway, inhibit mitochondrial oxidative phosphorylation, and increase glycolysis. GLUT1 is upregulated to increase glucose uptake by M1 microglia. Glucose oxidation through the pentose phosphate pathway (PPP) generates NADPH, which is the substrate for NOX2 and iNOS to produce ROS and NO, respectively. P2x7, the ATP receptor activation, and mitochondrial ROS trigger NLRP3 inflammasome activation and IL-1β and IL-18 release. Activation of microglial metabotropic (mGluR) and N-methyl-D-aspartate (NMDA) glutamate receptors (NMDAR) trigger M1 polarization. ASC, adaptor molecule apoptosis-associated speck-like protein containing a CARD.

Figure 3

Schematic representation of molecular mechanisms of microglia-mediated neurotoxicity. Classically (M1) activated microglia induce neurotoxicity by direct and indirect mechanisms, including the induction of neurotoxic astrocytes (A1), damage of the brain endothelium, promotion and intensification of inflammation, synaptic dysfunction, neuronal injury, and cell death. All these mechanisms contribute to cognitive impairments and acute neurological dysfunctions in SAE. (A) M1 microglia produce pro-inflammatory molecules such as IL-1β, IL-1α, IL-6, IL-12, IL-23, IL-17, IFN-γ, TNF-α, glutamate, C1q, NO, and ROS. The secretion of IL-1α, TNF-α, and C1q by M1 microglia induces A1-polarized astrocytes and contributes to BBB disruption and IL-33 release, enhancing the inflammatory response of activated microglia. The release of ROS, NO, and CCL2 increases the brain endothelium’s permeability and mediates BBB disruption. The generation of IL-1β, IL-12, IL-23, IL-17, IFN-γ, TNF-α, and glutamate can, in turn, activate surveying microglia and recruit immune cells from the periphery to the CNS, which amplifies the inflammatory signal, creating a vicious circle of sustained and amplified neuroinflammation. (B) M1 microglia effects on neuronal functions. The release of TNF-α and high levels of glutamate induce neuronal excitotoxicity and cell death. IL-1β release by activated microglia causes synaptic loss. ROS and NO promote peroxidation of membrane lipids and axonal damage. BBB, blood–brain barrier; IL, interleukin; C1q, complement component 1; NO, nitric oxide; ROS, reactive oxygen species; TNF, tumor necrosis factor; IFN, interferon.