The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Optimal Neutrophil Function: Observations From Three Species
Open accessAbstract
Neutrophils are essential effector cells of the innate immune system that have recently been recognized as thyroid hormone (TH) target cells. Cellular TH bioavailability is regulated by the deiodinase enzymes, which can activate or inactivate TH. We have previously shown that the TH inactivating enzyme type 3 deiodinase (D3) is present in neutrophils. Furthermore, D3 knockout (D3KO) mice show impaired bacterial killing upon infection. We hypothesized that D3 plays a role in neutrophil function during infection by actively regulating local TH availability. We measured TH concentrations in cerebrospinal fluid (CSF) from patients with bacterial meningitis and controls. Bacterial meningitis resulted in marked changes in CSF TH levels, characterized by a strong increase of thyroxine and reverse-triiodothyronine concentrations. This altered TH profile was consistent with elevated D3 activity in infiltrating neutrophils at the site of infection. D3 knockdown in zebrafish embryos with pneumococcal meningitis resulted in increased mortality and reduced neutrophil infiltration during infection. Finally, stimulated neutrophils from female D3KO mice exhibited impaired NADPH-oxidase activity, an important component of the neutrophil bacterial killing machinery. These consistent findings across experimental models strongly support a critical role for reduced intracellular TH concentrations in neutrophil function during infection, for which the TH inactivating enzyme D3 appears essential.
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NADPH-oxidase activity is impaired in stimulated neutrophils of DIO3 knock-out mice compared to wild type neutrophils.
“Furthermore, NADPH-oxidase activity is impaired in stimulated neutrophils of DIO3 knock-out mice compared to wild type neutrophils [35].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [35]
The section “D3KO neutrophils exhibit impaired NADPH oxidase activity” reports reduced activity after stimulation compared with WT neutrophils. However, Figure 3D and the Discussion specify that the effect occurred only in neutrophils from female mice, not male mice; the claim omits that limitation. Page numbers are not available in the supplied copy. (LLM, conf=0.88)
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- Authors
- van der Spek, A. H., Jim, K. K., Karaczyn, A., van Beeren, H. C., Ackermans, M. T., Darras, V. M., Vandenbroucke-Grauls, C. M. J. E., Hernandez, A., Brouwer, M. C., Fliers, E., van de Beek, D., & Boelen, A.
- Affiliations
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam UMC Location University of Amsterdam (NL)
- Maine Medical Center Research Institute (US)
- KU Leuven (BE)
- Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, the Netherlands
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine
- Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2017-11-24
- Volume
- 159
- Issue
- 2
- Pages
- 826-835
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC5774253
- OpenAlex
- W2770024834
- Cited by
- 33
- References
- 38
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 2
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- type 3 deiodinase, thyroid hormones, neutrophils, bacterial meningitis, pneumococcal meningitis, cerebrospinal fluid, thyroxine, reverse T3, NADPH oxidase, neutrophil function, innate immunity, zebrafish, bacterial killing
- MeSH terms
- Animals, Cells, Cultured, Embryo, Nonmammalian, Iodide Peroxidase, Neutrophils, Species Specificity, Thyroid Hormones, Triiodothyronine, Reverse, Zebrafish, Case-Control Studies, Meningitis, Bacterial, Mice, Knockout, Animals, Genetically Modified
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