CLIC1 supports mechanisms related to platelet activation and thrombosis

Background: Chloride intracellular channel 1 (CLIC1) is expressed in platelets, but CLIC1 action in these cells has not been clarified. Methods: CLIC1 function was probed in platelets in vitro as well as in a mouse dorsal skin fold chamber model in vivo to assess thrombus formation. Results: Co-localization of CLIC1 with F-actin was detected in lamellipodia of platelets, which relocate CLIC1 to their cell surface in an integrin-dependent manner. Treatment with the CLIC1 inhibitor IAA94 hindered CLIC1 relocation to the platelet membrane, diminished platelet aggregation and reduced integrin αIIbβ3 activation. Injecting mice with IAA94 delayed vaso-occlusion in a mouse model of photo-chemical thrombus formation in vivo. The role of CLIC1 for platelet activation could be reproduced in platelet concentrates, which even after prolonged storage expressed minimal CLIC1 on the platelet surface unless platelets were exposed to an activating stimulus. Conclusion: These data show that CLIC1 is regulated by adhesive interactions with integrin ligands that cause CLIC1 to relocate to the platelet cell surface. This process in turn appears to be relevant for integrin-mediated functions involved in platelet thrombus formation in vitro and in vivo. Moreover, CLIC1 has the potential to be a useful marker for monitoring the activation state of platelet concentrates during prolonged storage.