Hashimoto’s thyroiditis induces neuroinflammation and emotional alterations in euthyroid mice

Abstract

BackgroundAlthough studies have reported an increased risk for mood disorders in Hashimoto’s thyroiditis (HT) patients even in the euthyroid state, the mechanisms involved remain unclear. Neuroinflammation may play a key role in the etiology of mood disorders in humans and behavioral disturbances in rodents. Therefore, this study established a euthyroid HT model in mice and investigated whether HT itself was capable of triggering neuroinflammation accompanied by emotional alterations.MethodsExperimental HT was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Four weeks after the last challenge, mice were tested for anxiety-like behavior in the open field and elevated plus maze tests and depression-like behavior in the forced swimming and tail suspension tests. Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with neuroinflammation. The changes in components of central serotonin signaling were also investigated.ResultsHT mice showed intrathyroidal monocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function, which defines euthyroid HT in humans. These mice displayed more anxiety- and depressive-like behaviors than controls. HT mice further showed microglia and astrocyte activation in the frontal cortex detected by immunohistochemistry, real-time RT-PCR, and transmission electron microscopy (TEM). These observations were also accompanied by enhanced gene expression of proinflammatory cytokines IL-1β and TNF-α in the frontal cortex. Despite this inflammatory response, no signs of neuronal apoptosis were visible by the TUNEL staining and TEM in the frontal cortex of HT mice. Additionally, IDO1 and SERT, key serotonin-system-related genes activated by proinflammatory cytokines, were upregulated in HT mice, accompanied by reduced frontal cortex serotonin levels.ConclusionsOur results are the first to suggest that HT induces neuroinflammation and alters related serotonin signaling in the euthyroid state, which may underlie the deleterious effects of HT itself on emotional function.

Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases

“…In Hashimoto's thyroiditis mice, IDO1 and SERT are upregulated, accompanied by reduced frontal cortex 5-HT levels. This indicates that alterations in 5-HT signaling in the frontal cortex may be associated with mood control in Hashimoto's thyroiditis patients (107). In Balb/c mice of experimental antiphospholipid syndrome, nervous or mental abnormity such as cognitive deficits and hyperactivity are confirmed to be linked with the up-regulation of 5-HT 1A receptors in the hippocampal and cortical regions (108).…”

Correlation Between Hashimoto's Thyroiditis–Related Thyroid Hormone Levels and 25-Hydroxyvitamin D

“…Clinical studies have suggested that HT is associated with the occurrence of papillary thyroid carcinoma (3). One study suggested that in normal thyroid function, HT can also cause neuroinflammation, leading to emotional alterations (4). At present, the incidence of HT is also increasing; most patients do not show symptoms, often found in the physical examination.…”

Hashimoto’s thyroiditis impairs embryo implantation by compromising endometrial morphology and receptivity markers in euthyroid mice

“…Tg-induced thyroiditis in susceptible mice is a classic model of HT to explore the pathogenesis and therapeutics of HT [40]. A Tg-induced euthyroid HT mouse model previously established in our laboratory was used for the study [41]. Thus, to examine the isolated effect of euthyroid HT on embryo implantation, this study utilized female NOD mice immunized with porcine Tg, resulting in pronounced diffuse enlargement of the thyroid gland, the production of intrathyroidal mononuclear cell infiltration and rising serum Tg-Ab and TPO-Ab antibodies without accompanying FT3, FT4 and TSH abnormalities in serum and the local endometrium, which defines euthyroid HT in humans.…”