High Mobility Group Box 1 (HMGB1): Potential Target in Sepsis-Associated Encephalopathy

Abstract

Sepsis-associated encephalopathy (SAE) remains a challenge for intensivists that is exacerbated by lack of an effective diagnostic tool and an unambiguous definition to properly identify SAE patients. Risk factors for SAE development include age, genetic factors as well as pre-existing neuropsychiatric conditions. Sepsis due to certain infection sites/origins might be more prone to encephalopathy development than other cases. Currently, ICU management of SAE is mainly based on non-pharmacological support. Pre-clinical studies have described the role of the alarmin high mobility group box 1 (HMGB1) in the complex pathogenesis of SAE. Although there are limited data available about the role of HMGB1 in neuroinflammation following sepsis, it has been implicated in other neurologic disorders, where its translocation from the nucleus to the extracellular space has been found to trigger neuroinflammatory reactions and disrupt the blood-brain barrier. Negating the inflammatory cascade, by targeting HMGB1, may be a strategy to complement non-pharmacologic interventions directed against encephalopathy. This review describes inflammatory cascades implicating HMGB1 and strategies for its use to mitigate sepsis-induced encephalopathy.

Keywords: HMGB1; high mobility group box 1; sepsis; sepsis-associated encephalopathy.

Figure 1

Dynamic equilibrium of unbound and DNA-bound HMGB1 structure. Schematic representation of human HMGB1. The three domains are represented by colored boxes. Red: positively charged DNA-binding Boxes A and B, black: negatively charged acidic tail. Interactions between positively charged Boxes A and B and the negatively charged acidic tail regulate HMGB1 DNA-binding activities by competitive electrostatic interactions.

Figure 2

Anti-inflammatory activities of HMGB1. HMGB1 mediates several anti-inflammatory activities through binding to several receptors alone or in association with soluble mediators.

Figure 3

Microglial activation leading to neuroinflammation. Microglia can take on either anti- or pro-inflammatory phenotypes. In their pro-inflammatory state, cytokines, nitric oxide, excitatory neurotransmitters and metabolites (such as reactive oxygen species) are released in the brain parenchyma. Multiple experimental interventions have shown promising results in modulating microglial activity. In addition to the direct effects of microglial activation on neurons, neuroinflammation may also contribute to SAE through its effects on the microvasculature of the brain. Inflammation can lead to the formation of microthrombi in the brain, which can cause ischemia and further neuronal injury. Additionally, the activation of the complement cascade can lead to the formation of the membrane attack complex (MAC), which can damage the endothelial cells, leading to blood–brain barrier breakdown and increased permeability.