Platelet-derived HMGB1 is a critical mediator of thrombosis

Abstract

Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.

Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation

“…One hundred percent therapeutic windows, which directed new attention toward late-acting mediators such as high-mobility group box 1 protein (HMGB1) (6,9). HMGB1 is a highly conserved non-histone DNA binding nuclear protein, functioning as a damage-associated molecular pattern (DAMP) upon release by dying cells or activated immune cells (10)(11)(12). Once emitted into extracellular milieu, HMGB1 physically interacts with various receptors in immune cells.…”

“…Many of these therapeutic strategies focused on the attenuation of HMGB1-mediated proinflammatory response. However, recent studies have revealed that in addition to mediating late stage-inflammatory response by immune cells, HMGB1 signaling in platelets play a critical role in thrombus formation and other hyper-coagulation processes, which exacerbates tissue damage and aggravates severe sepsis (11,12,(20)(21)(22). In clinic, the serum level of HMGB1 and prognosis of organ failure appeared to be positively correlated in a septic patient with disseminated intravascular coagulopathy (DIC) (23).…”

“…Both LPS (38,39) and HMGB1 (11,12,20) have been suggested to induce coagulation, and each substance is considered as a single factor for aggravating tissue impairment in septic patients other signaling pathway or to interrupt other substances interacting TLR4.…”

Platelet HMGB1: the venous clot coordinator

“…Ferric chloride-induced thrombus formation in mesenteric arteries was attenuated in mice with a platelet-specific deletion of HMGB1, and blood from these mice was less thrombogenic in a collagen-coated flow chamber system. 6 Furthermore, HMGB1…”

“…6 Stark and colleagues identified activated platelets as the main source of HMGB1 in murine venous thrombosis. In a series of elegant experiments, the authors demonstrated that HMGB1 released from platelets promotes thrombosis in the inferior vena cava stenosis model by coordinating the crosstalk between platelets, monocytes, and neutrophils.…”