Abstract
We previously reported an early surge in high mobility group box protein 1 (HMGB1) levels in a polytrauma (PT) rat model. This study investigates the association of HMGB1 levels in mediating PT associated dysregulated immune responses and its influence on the cellular levels of receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). Using the same PT rat model treated with anti-HMGB1 polyclonal antibody, we evaluated changes in circulating inflammatory cytokines, monocytes/macrophages and T cells dynamics and cell surface expression of RAGE and TLR4 at 1, 3, and 7 days post-trauma (dpt) in blood and spleen. Notably, PT rats demonstrating T helper (Th)1 and Th2 cells type early hyper-inflammatory responses also exhibited increased monocyte/macrophage counts and diminished T cell counts in blood and spleen. In blood, expression of RAGE and TLR4 receptors was elevated on CD68+ monocyte/macrophages and severely diminished on CD4+ and CD8+ T cells. Neutralization of HMGB1 significantly decreased CD68+ monocyte/macrophage counts and increased CD4+ and CD8+ T cells, but not γδ+TCR T cells in circulation. Most importantly, RAGE and TLR4 expressions were restored on CD4+ and CD8+ T cells in treated PT rats. Overall, findings suggest that in PT, the HMGB1 surge is responsible for the onset of T cell exhaustion and dysfunction, leading to diminished RAGE and TLR4 surface expression, thereby possibly hindering the proper functioning of T cells.
Highlights
Published: 30 June 2021Polytrauma (PT) patients develop hyper-acute inflammatory responses involving cell death, the release of damage-associated molecular patterns (DAMPs) and immune dysregulation [1,2,3,4,5]
Findings suggest that in PT, the high mobility group box protein 1 (HMGB1) surge is responsible for the onset of T cell exhaustion and dysfunction, leading to diminished receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) surface expression, thereby possibly hindering the proper functioning of T cells
Current evidence suggests that persistent lymphopenia in severe trauma is associated with the development of multiple organ dysfunction syndrome (MODS), impaired fracture healing and increased mortality [5,10]
Summary
Polytrauma (PT) patients develop hyper-acute inflammatory responses involving cell death, the release of damage-associated molecular patterns (DAMPs) and immune dysregulation [1,2,3,4,5]. This response impacts patients, especially those with multiple injuries, including fractures, to have adverse clinical outcomes such as altered leukocyte kinetics and impaired fracture repair, in contrast to normal fracture healers [6,7]. Current evidence suggests that persistent lymphopenia in severe trauma is associated with the development of multiple organ dysfunction syndrome (MODS), impaired fracture healing and increased mortality [5,10] This evidence warrants of development of targeted approaches to restore a balanced immune response in PT patients to overcome the burden of deleterious outcomes
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