HMGB1 as a Therapeutic Target to Alleviate Endothelial Dysfunction in Severe Systemic Inflammation - Abstract
Excessive endothelial activation causing microvascular dysfunction is key in the pathogenesis of severe systemic inflammation. The ubiquitous nuclear protein high-mobility group box-1 (HMGB1) is extracellularly released as an alarmin and elicits potent proinflammatory effects on endothelial cells after sterile or infectious tissue injury. These effects include increased release of cytokines, chemokines, and factors promoting coagulation and fibrinolytic activities, and luminal endothelial expression of adhesion molecules. HMGB1 is actively discharged from innate immune cells, endothelial cells, and sensory-motor nerves innervating vascular compartments. Discrete HMGB1 redox isoforms signal via toll-like receptor 4 or receptor for advanced glycation end-products (RAGE) to induce inflammation. Furthermore, extracellular HMGB1 avidly complex-binds other extracellular proinflammatory molecules and these complexes are endocytosed via RAGE to the endolysosomal system in many cells, such as endothelial cells. Increased intralysosomal HMGB1 levels disrupt the lysosomal
membrane allowing HMGB1-transported co-molecules access to cognate cytoplasmic proinflammatory receptors and inflammasome systems. The subsequent intracellular activation causes endothelial cell pyroptosis, liberating potent procoagulant and proinflammatory molecules. Therapies based on HMGB1-binding antagonists have yielded mixed results in preclinical studies of systemic inflammation. Unsuccessful results were possibly caused by steric hindrance for HMGB1-binding antagonists due to HMGB1 complex formation. An alternative therapeutic strategy is to inhibit HMGB1 release, a process requiring acetylation of nuclear HMGB1 enabling cytoplasmic export. Increased histone deacetylase activity reduces HMGB1 release and is promoted by acetylcholine signaling via alpha 7 nicotinic acetylcholine receptors present on endothelial cells and sensory neurons. Invasive and non-invasive electrical vagus nerve stimulation activates and mobilizes acetylcholine-secreting anti-inflammatory T lymphocytes to the microvascular compartment. This review focuses on determining the role that the innate immune system and sensory nerves have on driving mechanisms of endothelial dysfunction via release of pathogenic extracellular HMGB1.