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Local Control of Thyroid Hormone Action 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 June 2024 | Viewed by 6625

Special Issue Editor


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Guest Editor
Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Universitätsklinikum Essen, Hufelandstr. 55, D-45147 Essen, Germany
Interests: thyroid hormone transport and action in health and disease
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2022 Special Issue “Local Control of Thyroid Hormone Action”.

Thyroid hormones (TH) regulate many cellular processes, including proliferation, differentiation, and mitochondrial activity. Thus, proper TH signaling is critical for the homeostasis of almost all tissues and essential for normal brain development. According to the classical view, cell-specific TH action is largely determined by circulating TH concentrations that, in turn, are predominantly regulated by the activity of the hypothalamus–pituitary–thyroid axis. The discovery of different (1) TH transporters facilitating TH access to target cells, (2) deiodinases activating or inactivating TH intracellularly, as well as (3) distinct TH receptors and modes of intracellular receptor signaling has challenged this view and has shifted the focus from systemic TH levels toward the molecular components controlling local TH action. A broader understanding of TH transporters, deiodinase, receptors and their (patho-)physiological regulation will shed light on the molecular mechanisms underlying rare as well as common diseases with distinct changes in local TH homeostasis. Such knowledge will pave the ground for the development of pharmacological tools that may ultimately result in novel therapeutic approaches by modulating TH signaling in a cell-specific manner.

This Special Issue of the International Journal of Molecular Sciences focuses on TH transporters, deiodinases, and TH receptors and welcomes both original research articles and reviews that address molecular mechanisms underlying local control of TH signaling in health and disease.

Prof. Dr. Heike Heuer
Guest Editor

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Keywords

  • TH receptors
  • deiodinases
  • TH transporters
  • canonical/noncanonical signaling
  • TH metabolism
  • pathophysiology
  • animal model
  • hiPSC

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Published Papers (3 papers)

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Research

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17 pages, 3609 KiB  
Article
The Differential Effect of a Shortage of Thyroid Hormone Compared with Knockout of Thyroid Hormone Transporters Mct8 and Mct10 on Murine Macrophage Polarization
by Esmée Hoen, Franka M. Goossens, Kim Falize, Steffen Mayerl, Anne H. van der Spek and Anita Boelen
Int. J. Mol. Sci. 2024, 25(4), 2111; https://doi.org/10.3390/ijms25042111 - 9 Feb 2024
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Abstract
Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters. To study the effect of TH and TH [...] Read more.
Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters. To study the effect of TH and TH transporters on macrophage polarization, specific proinflammatory and immunomodulatory markers were analyzed in bone marrow-derived macrophages (BMDMs) depleted of triiodothyronine (T3) and BMDMs with a knockout (KO) of Mct8 and Mct10 and a double KO (dKO) of Mct10/Mct8. Our findings show that T3 is important for M1 polarization, while a lack of T3 stimulates M2 polarization. Mct8 KO BMDMs are unaffected in their T3 responsiveness, but exhibit slight alterations in M2 polarization, while Mct10 KO BMDMs show reduced T3 responsiveness, but unaltered polarization markers. KO of both the Mct8 and Mct10 transporters decreased T3 availability and, contrary to the T3-depleted BMDMs, showed partially increased M1 markers and unaltered M2 markers. These data suggest a role for TH transporters besides transport of TH in BMDMs. This study highlights the complex role of TH transporters in macrophages and provides a new angle on the interaction between the endocrine and immune systems. Full article
(This article belongs to the Special Issue Local Control of Thyroid Hormone Action 2.0)
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33 pages, 11637 KiB  
Article
Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brains
by Ting Wang, Yu Wang, Ana Montero-Pedrazuela, Lucía Prensa, Ana Guadaño-Ferraz and Estrella Rausell
Int. J. Mol. Sci. 2023, 24(11), 9643; https://doi.org/10.3390/ijms24119643 - 1 Jun 2023
Cited by 2 | Viewed by 2548
Abstract
Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic [...] Read more.
Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway) and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment. Full article
(This article belongs to the Special Issue Local Control of Thyroid Hormone Action 2.0)
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Review

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20 pages, 1366 KiB  
Review
Local Thyroid Hormone Action in Brain Development
by Andrea Alcaide Martin and Steffen Mayerl
Int. J. Mol. Sci. 2023, 24(15), 12352; https://doi.org/10.3390/ijms241512352 - 2 Aug 2023
Cited by 4 | Viewed by 2945
Abstract
Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner [...] Read more.
Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems. Thus, the question as to how TH signaling is implicated in the development and maturation of different neurotransmitter and neuromodulator systems has gained increasing attention. In this review, we first summarize the current knowledge on the regulation of TH signaling components during brain development. We then present recent advances in our understanding on how altered TH signaling compromises the development of cortical glutamatergic neurons, inhibitory GABAergic interneurons, cholinergic and dopaminergic neurons. Thereby, we highlight novel mechanistic insights and point out open questions in this evolving research field. Full article
(This article belongs to the Special Issue Local Control of Thyroid Hormone Action 2.0)
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