The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Abstract

Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC.

Nrf2 promotes thyroid development and hormone synthesis

“…6 C-D). Interestingly, these observed changes are consistent with what has been described previously in adult Nrf2 KO mice (Chartoumpekis et al ., 2020).…”

“…Recent studies performed on adult mice thyroid glands demonstrated the role of Nrf2 as a direct controller of the thyroglobulin (Tg) expression and as a central actor of the thyroid gland stress defense system (Renaud et al ., 2019; Chartoumpekis et al ., 2020) Despite these important studies related with oxidative stress in mature thyroid follicular cells, we lack information on the potential role of Nrf2 during thyroid development. Here, using zebrafish embryos and mouse-embryonic stell cell (mESC)-derived thyroid follicles, we though to characterise the role of Nrf2/nrf2a during mammalian and non-mammalian thyroid development.…”

Keap1/Nrf2 Signaling Pathway

“…Therefore, investigations of the protective effects of Keap1/Nrf2 signaling that focus on specific tissues or organs are of great interest. Such studies have traditionally focused on tissues with detoxification functions such as the liver [ 6 , 7 ] but have also expanded to diverse tissues, including the kidney [ 8 , 9 ], skin [ 10 ], lung [ 11 ], colon [ 12 ], heart [ 13 ], nervous system [ 14 ], adipose tissue [ 15 ], pancreas [ 16 ] and thyroid [ 17 , 18 ], as evidenced by the respective tissue/organ-specific studies that are outlined below and comprise the majority of studies in the present Special Issue. Lastly, research on Nrf2 has expanded to encompass not only basic but also translational and clinical studies.…”

“…In a review article from my group, Thanas et al discuss the latest studies on the roles of Keap1/Nrf2 signaling in the thyroid gland, which range from regulation of thyroid physiology to implication as a protective factor against diverse disease states including hypothyroidism, thyroid autoimmunity, thyroid enlargement (goiter), hyperthyroidism and thyroid carcinoma [ 18 ]. In addition, in an original research paper from my group, Chartoumpekis et al describe the global gene expression pattern in the thyroid of mice in response to excess iodide; by studying wild-type and Nrf2 knock-out mice in parallel, it is conclusively shown that Nrf2 is critical for mounting protective antioxidant, anti-inflammatory/anti-autoimmune and anti-fibrosis transcriptional responses in this setting [ 17 ].…”

The Keap1/Nrf2 Signaling Pathway in the Thyroid—2020 Update

“…The results confirmed that iodide overload induces the Nrf2 cytoprotective response. The results also showed that iodide upregulates inflammatory, immune, and fibrosis pathways, and that these responses are exacerbated in the absence of Nrf2 [29]. The phenotypes of Nrf2 KO and Keap1 KD mice are summarized in Figure 2.…”