Journal Article

T Cell-Derived IL-17A Induces Vascular Dysfunction via Perivascular Fibrosis Formation and Dysregulation of ⋅NO/cGMP Signaling

Münzel, Thomas, Garlapati, Venkata, Schäfer, Katrin, Efentakis, Panagiotis, Schüler, Rebecca, Daiber, Andreas, Li, Huige, Waisman, Ari, Wenzel, Philip, Lagrange, Jérémy, Wild, Johannes, Oelze, Matthias, Kossmann, Sabine, Karbach, Susanne Helena, Molitor, Michael, Stamm, Paul

2019

Overview

Aims. The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation. Methods and Results. Chronic IL-17A overexpression in T cells (CD4-IL-17Aind/+ mice) resulted in elevated reactive oxygen species in the peripheral blood and a significant vascular dysfunction compared to control mice. The vascular dysfunction seen in the CD4-IL-17Aind/+ mice was only accompanied by a modest and nonsignificant accumulation of inflammatory cells within the vessel wall. Therefore, infiltrating myeloid cells did not serve as an explanation of the vascular dysfunction seen in a chronic IL-17A-driven mouse model. In addition to vascular dysfunction, CD4-IL-17Aind/+ mice displayed vascular fibrosis with highly proliferative fibroblasts. This fibroblast proliferation was induced by exposure to IL-17A as confirmed by in vitro experiments with primary murine fibroblastic cells. We also found that the ⋅NO/cGMP pathway was downregulated in the vasculature of the CD4-IL-17Aind/+ mice, while levels of protein tyrosine kinase 2 (PYK2), an oxidative stress-triggered process associated with T cell activation, were upregulated in the perivascular fat tissue (PVAT). Conclusions. Our data demonstrate that T cell-derived IL-17A elicits vascular dysfunction by mediating proliferation of fibroblasts and subsequent vascular fibrosis associated with PYK2 upregulation.

• Publisher: Hindawi Publishing Corporation,Hindawi,John Wiley & Sons, Inc
• Subject: Analysis / Animals / Aorta - metabolism / Aorta - pathology / Blood pressure / Cell Proliferation / Cloning / Coronary vessels / Cyclic GMP - metabolism / Cytokines / Down-Regulation / Endothelium, Vascular - physiopathology / Fibroblasts - cytology / Fibroblasts - metabolism / Fibrosis / Flumazenil / Focal Adhesion Kinase 2 - metabolism / Hypertension / Inflammation / Interleukin-17 - genetics / Interleukin-17 - metabolism / Interleukins / Kinases / Life Sciences / Lung diseases / Lymphocytes / Male / Mice / Mice, Inbred C57BL / Neutrophils / Nitric oxide / Nitric Oxide - metabolism / Nitrogen / Oxidative stress / Phosphorylation / Physiology / Protein Subunits - metabolism / Psoriasis / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal Transduction / Skin / Skin diseases / Smooth muscle / Soluble Guanylyl Cyclase - metabolism / T cells / T-Lymphocytes - cytology / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Up-Regulation / Vitamin E