Oxidative Stress-Induced Sirtuin1 Downregulation Correlates to HIF-1α, GLUT-1, and VEGF-A Upregulation in Th1 Autoimmune Hashimoto's Thyroiditis.

Michaël Hepp,Alexis Werion,Benoit Lengelé,Chantal Daumerie,Axel De Greef,Julie Craps,Christine De Ville De Goyet,Marc De Bournonville,Marie-Christine Many,Catherine Behets,Marian Ludgate,Michel Mourad,Virginie Joris

doi:10.3390/ijms22083806

Abstract

In Hashimoto’s thyroiditis (HT), oxidative stress (OS) is driven by Th1 cytokines’ response interfering with the normal function of thyrocytes. OS results from an imbalance between an excessive production of reactive oxygen species (ROS) and a lowering of antioxidant production. Moreover, OS has been shown to inhibit Sirtuin 1 (SIRT1), which is able to prevent hypoxia-inducible factor (HIF)-1α stabilization. The aims of this study were to determine the involvement of NADPH-oxidases (NOX), SIRT1, and HIF-1α in HT pathophysiology as well as the status of antioxidant proteins such as peroxiredoxin 1 (PRDX1), catalase, and superoxide dismutase 1 (SOD1). The protein expressions of NOX2, NOX4, antioxidant enzymes, SIRT1, and HIF-1α, as well as glucose transporter-1 (GLUT-1) and vascular endothelial growth factor A (VEGF-A), were analyzed by Western blot in primary cultures of human thyrocytes that were or were not incubated with Th1 cytokines. The same proteins were also analyzed by immunohistochemistry in thyroid samples from control and HT patients. In human thyrocytes incubated with Th1 cytokines, NOX4 expression was increased whereas antioxidants, such as PRDX1, catalase, and SOD1, were reduced. Th1 cytokines also induced a significant decrease of SIRT1 protein expression associated with an upregulation of HIF-1α, GLUT-1, and VEGF-A proteins. With the exception of PRDX1 and SOD1, similar results were obtained in HT thyroids. OS due to an increase of ROS produced by NOX4 and a loss of antioxidant defenses (PRDX1, catalase, SOD1) correlates to a reduction of SIRT1 and an upregulation of HIF 1α, GLUT-1, and VEGF-A. Our study placed SIRT1 as a key regulator of OS and we, therefore, believe it could be considered as a potential therapeutic target in HT.

Highlights

In primary cultures of human thyroid cells, Th1 cytokines induce an increase in NOX4 known to generate H2 O2 and superoxide as well as a decrease in antioxidant proteins, peroxiredoxin 1 (PRDX1), catalase, and superoxide dismutase 1 (SOD1), responsible for oxidative stress (OS)
This is associated with a downregulation of Sirtuin 1 (SIRT1) protein expression and an upregulation of hypoxia-inducible factor (HIF)-1α, glucose transporter1 (GLUT-1), and vascular endothelial growth factor A (VEGF-A)
Our results showed a decrease of SIRT1 in Th1-treated human thyroid cells and in Hashimoto’s thyroids, suggesting that a significant interaction between reactive oxygen species (ROS) and SIRT1 exists in Hashimoto’s thyroiditis (HT)

Summary

Introduction

HT is the principal cause of creativecommons.org/licenses/by/ 4.0/). Hypothyroidism and goiter in a population where the diet supplies a sufficient iodine level [1]. In 90% of HT patients, high serum levels of thyroid peroxidase antibodies are detectable, whereas increased concentrations of serum thyroglobulin antibodies are present in only 20% to 50% of such cases [2]. The known autoimmune reaction in HT implicates antibody-producing B lymphocytes as well as T cells. CD4+ T lymphocytes play a key role in the pathogenesis of HT leading to T helper type 1 (Th1) stimulation. Th1 cytokines, such as interferon (IFN)γ, interleukin (IL)-1α, IL-1β, Il-2, tumor necrosis factor (TNF)-α, and TNF-β, trigger thyrocyte destruction by CD8+ cytotoxic cells, which leads to gland atrophy and hypothyroidism [3]

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