Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

Abstract

Hypertension (HTN) is an established risk factor for subsequent cardiovascular diseases, with Angiotensin II (Ang-II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and interleukin-6 (IL-6) play an important role in adaptive immune responses, little is known about their role(s) in the thrombo-inflammatory responses associated with Ang-II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1 −/−) and IL-6 deficient (IL-6 −/−) mice are afforded protection against Ang-II induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang-II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6 −/−-derived T cells into Rag-1 −/− mice failed to accelerate Ang-II-induced thrombosis compared to Rag-1 −/− mice reconstituted with WT-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang-II HTN. Interestingly, adoptive transfer of WT T cells into Rag-1 −/− /Ang-II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population i.e. pro-thrombotic and pro-inflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R and T cell-dependent IL-6 signaling in Ang-II induced thrombo-inflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of HTN.

Plasma Fibrinogen, D-dimer, and Fibrin Degradation Product as Biomarkers of Rheumatoid Arthritis

“…A previous study revealed that IL-6 could mediate thrombocytosis, platelet hyperreactivity, and accelerate extra-intestinal thrombosis associated with experimental colitis [11]. Another study showed that IL-6 and T-cell-dependent IL-6 signaling was involved in angiotensin II-induced thromboin ammation [12]. As one of the most important members in the coagulation system, tissue factor could also mediate the production of pro-in ammatory cytokines by activating protease-activated receptors on various cells such as mononuclear cells, endothelial cells, platelets, and so on [13].…”

Pathological Role of Angiotensin II in Severe COVID-19

“…There is also accelerated microvascular thrombosis in arterioles and to a lesser extent in venules after Ang II infusions. 53 Clinical data also support the role of Ang II in fibrinolysis. Plasminogen activator inhibitor 1 (PAI-1) is the major inhibitor of the fibrinolytic system and elevated levels have been found to be associated with coronary artery disease, deep vein thrombosis, and malignancy.…”

Premorbid IL-6 levels may predict mortality from COVID-19

“…IL-6 upregulates cathepsin L production 4 , which then cleaves the virus, enabling it to infect pulmonary epithelial cells 3 . IL-6 also upregulates the Angiotensin II AT1 receptor 17 , and likely upregulates pulmonary epithelial cell ACE2 receptors, with a positive correlation between IL-6 and ACE2 levels in bronchioalveolar lavage (BAL) in patients with severe acute pulmonary in ammation 5 . Viral reproduction within pulmonary epithelial cells then recruits in ammatory cells which, in turn produce cytokines (as part of the "cytokine storm" phenomenon 18 ) including IL-6.…”