Megakaryocytes possess a STING pathway that is transferred to platelets to potentiate activation.

Platelets display unexpected roles in immune and coagulation responses. Emerging evidence suggests that STING is implicated in hypercoagulation. STING is an adaptor protein downstream of the DNA sensor cyclic GMP-AMP synthase (cGAS) that is activated by cytosolic microbial and self-DNA during infections, and in the context of loss of cellular integrity, to instigate the production of type-I IFN and pro-inflammatory cytokines. To date, whether the cGAS-STING pathway is present in platelets and contributes to platelet functions is not defined. Using a combination of pharmacological and genetic approaches, we demonstrate here that megakaryocytes and platelets possess a functional cGAS-STING pathway. Our results suggest that in megakaryocytes, STING stimulation activates a type-I IFN response, and during thrombopoiesis, cGAS and STING are transferred to proplatelets. Finally, we show that both murine and human platelets contain cGAS and STING proteins, and the cGAS-STING pathway contributes to potentiation of platelet activation and aggregation. Taken together, these observations establish for the first time a novel role of the cGAS-STING DNA sensing axis in the megakaryocyte and platelet lineage.

Who and how, DNA sensors in NETs-driven inflammation.

During infections, neutrophil extracellular traps act like a meshwork of molecules that captures microbes. In contrast, during sterile inflammation the presence of NETs is usually associated with tissue damage and uncontrolled inflammation. In this context, DNA acts both as activator of NETs formation and immunogenic molecule fueling inflammation within the injured tissue microenvironment. Pattern recognition receptors that specifically bind to and get activated by DNA such as Toll-like receptor-9 (TLR9), cyclic GMP-AMP synthase (cGAS), Nod-like receptor protein 3 (NLRP3) and Absence in Melanoma-2 (AIM2) have been reported to play a role in NETs formation and detection. However, how these DNA sensors contribute to NETs-driven inflammation is not well understood. Whether these DNA sensors have unique roles or on the contrary they are mostly redundant is still elusive. In this review, we summarize the known contribution of the above DNA sensors to the formation and detection of NETs in the context of sterile inflammation. We also highlight scientific gaps needed to be addressed and propose future direction for therapeutic targets.