High-mobility group box 1 (HMGB1), long recognized for its main role in mediating sterile inflammation, has been lately studied as a stimulator in platelet activation through Toll-like receptor 4.
Beyond its intracellular functions, extracellular HMGB1 actively contributes to immune signaling and plays a significant role in thromboinflammatory disorders such as sickle cell disease (SCD).
HMGB1 potentiates ADP-P2Y12 signaling in platelets
Recent findings reveal that HMGB1 enhances platelet activation by modulating purinergic signaling pathways. Specifically, HMGB1 significantly amplifies ADP-mediated platelet activation through the P2Y12 receptor. This effect is achieved not through de novo synthesis, but via increased surface expression of P2Y12, thereby priming platelets for a heightened response to ADP (adenosine diphosphate).
Mechanistic studies demonstrate that HMGB1 stimulates endogenous ADP secretion and interacts synergistically with ADP to promote platelet activation. Inhibition of P2Y12 attenuates this activation, underscoring the receptor’s pivotal role in HMGB1-induced thrombogenic responses. Plasma from SCD patients can replicate this effect in platelets from healthy donors, suggesting a systemic role for circulating HMGB1 in modulating platelet responsiveness
This crosstalk between inflammatory and thrombotic signaling underscores HMGB1’s dual role as both a direct platelet agonist and an enhancer of other activation pathways. The study offers key insights into the pathophysiology of thromboinflammatory diseases and highlights novel therapeutic opportunities targeting HMGB1 and P2Y12 signaling axes.
Targeting HMGB1-TLR4 or HMGB1-RAGE interactions may provide a complementary approach to modulate thromboinflammatory responses.
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Read the full article about the study:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10972595/
