| Popis: |
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. |
