Rôles de la cavéoline-1 et des antioxydants dans l'homéostasie des cellules thyroïdiennes et des cellules musculaires squelettiques
(2010)
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- Abstract
- (en) H2O2, produced by dual oxidases (Duox), is an absolute requirement for thyroid hormone synthesis. To avoid the toxic effect of H2O2, the best protection of the thyroid cell is the localization of the H2O2 production site outside the cell, at the interface with the colloid. That has been recently reinforced by the concept of “thyroxisome”, the unit of thyroid hormone synthesis. The thyroxisome is a multimeric complex, made of at least TPO and Duox, and it permits to restrain the iodination process at the apical pole of the cell. In the first part of this work, we hypothesize that caveolin-1 could be implicated in the thyroxisome formation. Indeed, caveolin-1, expressed at the apical pole of thyrocytes and regulated by TSH, is well known in different cell types to be implicated in the compartmentalization of a variety of cell processes. In caveolin-1 KO mice, we show that thyroglobulin (Tg), Duox, and TPO transport is impaired, and that these proteins are localized in the cytoplasm. This thyroxisome disruption leads to thyroid alterations, 50% of the follicle lumina being empty. The localization of I127, iodinated Tg, and TPO inside the cell indicates that the iodination process occurs in the cytoplasm rather than in the colloid. In the second part of this work, we studied how the loss of a component of the thyroid hormone synthesis machinery could have an effect on the thyroid cell homeostasis. Indeed, in order to maintain an appropriate location of iodination process, all partners must be present at the proper place. An important component is iodide which is transported across the apical membrane probably by pendrin. Pendred disease is characterized by mutation in Pendred gene leading to deficiency in pendrin. We show that the Pendred thyroid contains numerous altered follicles without iodinated Tg and T4, but with an intracellular localization of Duox, TPO and T4 associated with a loss of caveolin-1, while others show a normal iodination. We conclude that the loss of pendrin leads to thyroxisome disruption. In thyroids of both KO caveolin-1 mice and Pendred patient, the intracellular iodination is associated with high oxidative stress (OS), and increased expression of antioxidant enzymes like peroxiredoxins (PRDXs) and catalase. This high OS leads to apoptosis, partially compensated by increased proliferation. This association of increased proliferation and absence of caveolin-1 expression confirms the negative role played by caveolin-1 on thyrocytes proliferation. If apoptosis rate becomes more important than the proliferation one, the follicular destruction increases and induces severe hypothyroidism. In the third part of this work, we analyzed the effect of a chronic TSH stimulation on thyroid cell homeostasis. In Graves’ disease, while the hyperstimulation of TSH receptor (TSHR) by autoantibodies induces an overexpression, but with a correct localization of thyroxisome components, the thyroxisome integrity is maintained. This induces an increased hormonal synthesis associated with higher OS which remains yet not toxic, but correctly compensated by antioxidants. The Graves’ disease is often associated with a thyroid ophthalmopathy (TAO) induced by TSHR autoantibodies. Indeed TSHR is expressed by both thyrocytes and orbital fibroblasts. Interactions between these fibroblasts and infiltrating lymphocytes induce fibrosis and adipogenesis leading finally to dissociation of skeletal muscle cells. In this work, we show that muscle cells as well as adipocytes coming from TAO patients undergo OS, compensated by increased PRDXs and catalase expression, or leading to apoptosis. We show also that in case of TAO, the expression of adiponectin by muscular cells is increased as well as its regulator, PPARgamma. Thus, we suggest that adiponectin could play a role as an antioxidant. In conclusion, in order to maintain the thyroid cell homeostasis, a strict localization of H2O2 production within the thyroxisome, most likely brought together by caveolin-1, is absolutely required. To keep cell homeostasis, all proteins participating in hormone synthesis must be active and correctly localized in order to avoid cytoplasmic accumulation of iodide that may lead to OS and cell apoptosis. These conclusions obtained by our study on KO caveolin-1 mice and on Pendred thyroid are reinforced by the study of Graves’ disease where the chronically stimulated iodination machinery, as well as caveolin-1, is correctly localized. In this case, the OS is not toxic but well compensated by antioxidants. The increased adiponectin levels observed in Graves’ disease and TAO could be implicated in this antioxidant defense.
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Citations
Senou, M. (2010). Rôles de la cavéoline-1 et des antioxydants dans l’homéostasie des cellules thyroïdiennes et des cellules musculaires squelettiques. https://hdl.handle.net/2078.5/45936