Interleukin-6 enhances localized immune cell infiltration and deep vein thrombosis resolution at the distal edge

Inflammation directed by immune cells is pivotal in the development of deep vein thrombosis (DVT). Disruption in the infiltration of these cells can lead to dysregulation of thrombus organization and increase the risk of deadly embolization. Although the general importance of the cytokine interleukin-6 (IL-6) in immune responses is well documented, its role in acute DVT remains largely unknown. Here, we elaborate on how IL-6 governs acute inflammation and the subsequent organization and early resolution of DVT in vivo. We induced DVT in mice via total inferior vena cava ligation and infused them with either recombinant IL-6 or phosphate-buffered saline (PBS) as a control. Exogenous IL-6 reduced DVT burden by 2 and 4 days with accelerated distal edge organization, characterized by well-demarcated fibrosis-like white lesions containing abundant fibrin-collagen, neutrophils, platelets, Arg1⁺ monocytes, von Willebrand factor, laminin, myofibroblasts, and neovascular channels at the expense of erythrocytes. IL-6 upregulated intrathrombi chemokines, proinflammatory cytokines, and platelet-leukocyte surface markers in the distal region. This IL-6-heightened localized inflammatory response led to extracellular matrix remodeling, which is essential for DVT organization and early resolution. As observed by two-photon microscopy in stasis- and irradiation-induced saphenous vein thrombosis, IL-6 stimulated leukocytes to rapidly infiltrate the thrombus in parallel with venous flow through the distal edge. IL-6-augmented thrombus organization, visualized by rhodamine 6 G-labeled platelet-leukocyte accumulation, prompted early resolution, as determined by the reduced thrombus area. Ultimately, IL-6 enhances DVT organization by amplifying localized leukocyte migration and orchestrating acute inflammation involving platelets, thereby expediting the early resolution of DVT.NEW & NOTEWORTHY IL-6 might play a beneficial role in acute DVT by coordinating the actions of innate leukocytes and platelets. This coordination enhances acute inflammation-dependent thrombus organization at specific distal locations, facilitating early resolution and reducing the burden of acute DVT. Although the role of inflammation in the pathogenesis of DVT remains controversial, our results indicate that IL-6 exerts an antithrombotic effect in acute DVT.