Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution

Abstract

Deep vein thrombosis (DVT) is the most common type of venous thromboembolism. Patients with DVT are at risk of developing potentially life-threatening complications, such as pulmonary embolism, but also long-term complications, including post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension.1 Current treatments for DVT focus on preventing clot expansion with anticoagulants and vasoactive drugs and by increasing venous blood flow through physical methods. However, anticoagulation cannot accelerate the natural thrombus resolution and reciprocally increases the risk of bleeding. Despite initial management of symptomatic acute events, patients remain at high risk for recurrence and predisposed to developing long-term complications. Transition of thromboembolic events to chronic disease is essentially caused by persistent inflammation resulting in delayed thrombus resolution, fibrosis, and vessel wall damage. Conclusions: T EM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.

Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis

“…In addition, Luther et al . recently confirmed that IFN‐γ delays thrombus neovascularization and resolution . IFN‐γ is an inflammatory cytokine produced by immune cells, and promotes inflammatory processes such as macrophage activation, and expression of chemokines and adhesion molecules involved in the recruitment of immune cells.…”

“…Nosaka et al showed that IFN-c delays thrombus resolution by inhibiting matrix metalloproteinase-9 production by monocytes, and Schonfelder et al demonstrated that absence of Tbet accelerates thrombus resolution by inhibiting interleukin-12 formation by monocytes [21,27]. In addition, Luther et al recently confirmed that IFN-c delays thrombus neovascularization and resolution [22]. IFN-c is an inflammatory cytokine produced by immune cells, and promotes inflammatory processes such as macrophage activation, and expression of chemokines and adhesion molecules involved in the recruitment of immune cells.…”

“…It was found that neutrophils had increased sensitivity to interferon (IFN)-c and that, in vitro, IFN-c induced the formation of NETs by neutrophils [17]. IFN-c is a proinflammatory cytokine that has been implicated in several cardiovascular diseases, including hypertension, atherosclerosis, angiogenesis, and venous thrombosis [18][19][20][21][22]. Therefore, we hypothesize that, in the context of venous thrombosis, IFN-c triggers NET formation with subsequent venous thrombosis development.…”

Acute deep vein thrombosis suppresses peripheral T cell effector function

“…The cross‐talk of T cells with endothelium and coagulation proteins (such as thrombin) suggest a pivotal role of the immune system for coagulatory homoeostasis and the pathophysiology of venous thrombosis (Naldini et al , ; Carman & Martinelli, ). In contrast to the recently described role of T cells in thrombi (Luther et al , ), potential effects of DVT on systemic immune cell function have rarely been studied. Although recent observations indicate a link between venous thrombosis and changes in systemic immunity (Keragala et al , ), it remains unclear whether immune alterations are the cause or consequence of DVT and how they correlate with the severity of disease.…”

Unexpected role of natural killer cell‐derived interferon‐γ as a driver of NETosis and DVT

“…But are NK cells really the only relevant source of IFN‐γ in DVT, as is implied by the NK cell depletion experiments of Bertin and coworkers? This aspect certainly needs further clarification, as in particular effector memory T‐cells were demonstrated to be crucial for the early inflammatory response in the same IVC ligation model and additional relevant sources of IFN‐γ could be involved . In addition to the NETosis‐related growth of inferior vena cava thrombi, at later stages T‐bet and IFN‐γ serve as critical elements in the resolution of IVC thrombi .…”