Associate professor Université Du Québec à Trois-RIvières Trois-Rivieres, Quebec, Canada
Background: During infections, platelets have key roles in bridging together immune responses and coagulation. Upon stimulation of immune receptors platelets directly respond to pathogens and communicate with other immune cells by secreting inflammatory molecules. However, in specific inflammatory conditions, the crosstalk between platelet and immune responses lead to tissue damage and uncontrolled coagulation in a process called immunothrombosis. In nucleated cells, the activation of the immune receptor cGAS by Self- or microbial-DNA results in the production of cGAMP, that binds to and activates the adaptor protein STING to induce the production of type-I Interferon and other pro-inflammatory cytokines. Interestingly, STING activation has been reported to contribute to immunothrombosis during sepsis and COVID-19.
Aims: However, it is currently unknown whether the proteins from the cGAS-STING pathway are expressed in platelets and their mother cells the megakaryocytes. To fill this gap, we characterized the presence and function of these proteins in both cell populations.
Methods: To complete this study, we relied on platelets and bone marrow megakaryocytes isolated from wt and cGAS-/- mice.
Results: Here, we reveal for the first time that the proteins from the cGAS-STING pathway are expressed and functional in mouse bone marrow megakaryocytes. As such, STING stimulation of megakaryocytes drives the production of CCL5 and of type-I Interferon, both critical regulators of hematopoiesis. We also report that mouse platelets express cGAS, which produces cGAMP upon DNA stimulation. Furthermore, we reveal that cGAS and STING stimulation of platelets potentiates the aggregation of platelets and the membrane translocation of P-selectin.
Conclusion(s): Taken together, our data unveil a new and intriguing role for the cGAS-STING axis in megakaryocytes and platelets and suggest that activation of cGAS and STING could contribute to both immune responses and coagulation. Whether this pathway directly fuels immunothrombosis will however necessitate further studies.
