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

Abstract

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.

• Authors: Rebecca Schüler, Panagiotis Efentakis, Johannes Wild, Jérémy Lagrange, Venkata Garlapati, Michael Molitor, Sabine Kossmann, Matthias Oelze, Paul Stamm, Huige Li, Katrin Schäfer, Thomas Münzel, Andreas Daiber, Ari Waisman, Philip Wenzel, Susanne Helena Karbach
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2019 Pg. 6721531 ( 2019) ISSN: 1942-0994 [Electronic] United States
• PMID: 31396305 (Publication Type: Journal Article)

Chemical References

• Interleukin-17
• Protein Subunits
• Reactive Oxygen Species
• Nitric Oxide
• Focal Adhesion Kinase 2
• Soluble Guanylyl Cyclase
• Cyclic GMP

Topics

• Animals
• Aorta (metabolism, pathology)
• Cell Proliferation
• Cyclic GMP (metabolism)
• Down-Regulation
• Endothelium, Vascular (physiopathology)
• Fibroblasts (cytology, metabolism)
• Fibrosis
• Focal Adhesion Kinase 2 (metabolism)
• Interleukin-17 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (metabolism)
• Protein Subunits (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Soluble Guanylyl Cyclase (metabolism)
• T-Lymphocytes (cytology, immunology, metabolism)
• Up-Regulation