Paracrine signaling by glial cell–derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells

Abstract

Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…10) (173). Such a system has been used to demonstrate that paracrine signaling by glial cellderived T 3 activates neuronal gene expression.…”

“…The activity of the deiodinases can modify T 3 levels in a cell-specific fashion without affecting circulating thyroid hormone levels (84). A disruption in the D2 pathway has been shown to decrease T 3 production locally and disrupt thyroid hormone signaling in D2-expressing cells (92,173,(232)(233)(234). This is illustrated by the approximately 50% reduction in T 3 content in the D2 KO brain (187).…”

“…Intraperitoneal administration of LPS to rats (371-373) or mice (173) has been used extensively to promote central hypothyroidism and NTI (374). Despite the drop in serum thyroid hormone levels, both TRH expression in the paraventricular nucleus and serum TSH are decreased in LPS-treated rats, resembling the euthyroid sick syndrome (371,373).…”

“…Given that D2 is expressed in glial cells and TR mostly in neurons, the MCT8 inactivating mutation is thought to promote neuronal hypothyroidism by disrupting the paracrine effects of glia-made T 3 at a critical time for CNS development. In fact, the existence of this paracrine mechanism was verified in cocultures of glia and neuronal cell lines (173). Clinical evidence supporting this mechanism was first obtained in patients with severe neurological phenotype exhibiting the Allan-Herndon-Dudley syndrome (107,108).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…A paracrine paradigm for T3 supply is thought to occur in the central nervous system: D2 is highly expressed in glial cells providing T3 for neurons, which have higher D3 than D2 activity (34). This paracrine response is present in vivo as well, since the systemic administration of LPS, which induces a rapid increase of D2 in the tanycytes of the mediobasal hypothalamus and a consequent suppression of TRH expression (38), is absent in D2KO mice (39).…”