Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain
- University of Chicago Medical Center, United States
- Institute of Experimental Medicine, Hungary
- University of Chicago, United States
Abstract
The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for supplementary figures 2
Article and author information
Author details
Federico Salas-Lucia
Funding
The Hungarian National Brain Research Program 2 (NRDIO K125247)
- Csaba Fekete
National Institute of Diabetes and Digestive and Kidney Diseases (DK58538)
- Balázs Gereben
National Institute of Diabetes and Digestive and Kidney Diseases (DK58538,DK65055)
- Antonio Bianco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rauf Latif, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee at the University of Chicago (#72577) or by the Animal Welfare Committee at the Institute of ExperimentalMedicine and followed the American Thyroid Association Guide to investigating TH economy and action in rodents and cell models (52).
Version history
- Received: August 13, 2022
- Preprint posted: August 18, 2022 (view preprint)
- Accepted: May 18, 2023
- Accepted Manuscript published: May 19, 2023 (version 1)
- Version of Record published: June 5, 2023 (version 2)
Copyright
© 2023, Salas-Lucia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain
eLife 12:e82683.
https://doi.org/10.7554/eLife.82683
Further reading
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Adverse effects of proton pump inhibitors (PPIs) have raised wide concerns. The association of PPIs with influenza is unexplored, while that with pneumonia or COVID-19 remains controversial. Our study aims to evaluate whether PPI use increases the risks of these respiratory infections.
Methods:
The current study included 160,923 eligible participants at baseline who completed questionnaires on medication use, which included PPI or histamine-2 receptor antagonist (H2RA), from the UK Biobank. Cox proportional hazards regression and propensity score-matching analyses were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).
Results:
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Conclusions:
PPI users are associated with increased risks of influenza, pneumonia, as well as COVID-19 severity and mortality compared to non-users, while the effects on pneumonia or COVID-19-related outcomes under PPI use were attenuated when compared to the use of H2RAs. Appropriate use of PPIs based on comprehensive evaluation is required.
Funding:
This work is supported by the National Natural Science Foundation of China (82171698, 82170561, 81300279, 81741067, 82100238), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), the Guangdong Basic and Applied Basic Research Foundation (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People’s Hospital (DFJH201923, DFJH201803, KJ012019099, KJ012021143, KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).
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