Quercetin inhibits platelet activation and ER-stress mediated autophagy in response to extracellular histone

Cellular histones are DNA-binding nuclear proteins involved in chromatin remodelling and regulation of gene expression. However, extracellular histones act as damage-associated molecular patterns (DAMPs) and contribute to multiorgan damage in conditions with sepsis and diseases with acute critical illnesses. Alongside, histones are associated with thrombocytopenia due to dysfunctional platelets that regulate hemostasis and thrombosis. There is no drug available to prevent histone-induced platelet toxicity. Therefore, we for the first time examined quercetin (QUE) as a novel therapeutic to protect histone-induced platelet toxicity.

To delineate how histones induce platelet toxicity and investigate the protective efficacy of quercetin (QUE), a natural dietary phytochemical.

Histone-treated platelets were evaluated for platelet aggregation/activation markers, various autophagy-related signaling proteins, and cytotoxicity in vitro. For the inhibition study, QUE and other standard inhibitors were pre-treated before stimulation with histones. Further, we injected histones into mice in the presence or absence of QUE and evaluated the tail bleeding, lung toxicity, and circulatory platelet stress markers. Additionally, QUE-treated mice were challenged for histone-primed Collagen-epinephrine-induced pulmonary thromboembolism.

Extracellular histones induce platelet activation and aggregation by interacting with sialic acid in TLR1/2 or TLR4. Also, we have demonstrated for the first time that histones induce ER stress-mediated autophagy in platelets. QUE inhibited histone-induced platelet activation, aggregation, and ER-stress-mediated autophagy in response to histone treatment. Ex vivo experiments indicate that oral administration of QUE can safeguard platelets while concurrently mitigating their response to histone stimulation. In addition, quercetin increased the survival rates of histone-primed, collagen-epinephrine-induced acute pulmonary thromboembolism in mice.

In summary, this study demonstrated the beneficial effect of QUE in protecting platelets with possible implications for addressing histone-accelerated pathologies.