Abstract
Aseptic surgical trauma provokes the release of HMGB1, which engages the innate immune response after binding to pattern-recognition receptors on circulating bone marrow-derived monocytes (BM-DM). The initial systemic inflammation, together with HMGB1, disrupts the blood–brain barrier allowing penetration of CCR2-expressing BM-DMs into the hippocampus, attracted by the chemokine MCP-1 that is upregulated by HMGB1. Within the brain parenchyma quiescent microglia are activated and, together with the translocated BM-DMs, release proinflammatory cytokines that disrupt synaptic plasticity and hence memory formation and retention, resulting in postoperative cognitive decline (PCD). Neutralizing antibodies to HMGB1 prevents the inflammatory response to trauma and PCD.
Highlights
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All three HMGB genes are expressed during development; while HMGB1 is highly expressed in all adult tissues except in brain neurons, HMGB2 and −3 are only active in testis and lymphoid organs at the adult stage [3]
In a Traumatic Brain Injury (TBI) model, rats that were treated after injury with glycyrrhizin expressed lower levels of HMGB1 in microglia/macrophages and the activated microglia changed to the M2 reparative phenotype 5 days after TBI [71]
Summary
The HMGB protein family is composed of three members (HMGB1, −2 and −3), is evolutionarily conserved from metazoans to mammals and originally arose from the fusion of intronless genes [2]. HMGB1 has a tripartite domain organization with two HMG boxes A and B, connected by a short linker and followed by an acidic C-terminal sequence composed of 30 aspartate and glutamate residues. The acidic C-terminal sequence forms a flexible structure that can interact with specific positions within and between the HMG boxes and modulate DNA-binding capacities and helix-distorting activity. These intramolecular interactions compete with HMGB1 interactions with other protein partners and regulate HMGB1 biological functions [6]. A proposed three-dimensional structural representation (Figure 2) suggests that HMGB1 exists in a dynamic equilibrium between an “open” form that can interact with DNA and a more closed form in which DNA binding domains are occluded. Thomas], [Tail-Mediated Collapse of HMGB1 Is Dynamic and Occurs via Differential Binding of the Acidic Tail to the A and B Domains]; published by [Elsevier, 2010], [7]
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