Impaired Bacterial Clearance in Type 3 Deiodinase-Deficient Mice Infected with Streptococcus pneumoniae
Open accessAbstract
The activation of type 3 deiodinase (D3) has been postulated to play a role in the reduction of thyroid hormone levels during illness. Using a mouse model of acute bacterial infection, we have recently demonstrated marked D3 immunostaining in neutrophils infiltrating infected organs. These observations suggest a possible additional role for this enzyme in the innate immune response. To further assess the role of D3 in the response to acute bacterial infection, we used null D3 [D3 knockout (D3KO)] and wild type (WT) mice and infected them with Streptococcus pneumoniae. Marked reductions in serum thyroid hormone levels were observed both in D3KO and WT mice. Infection resulted also in a decrease in liver D1 activity in WT, but not in infected D3KO mice. Upon infection, pulmonary neutrophilic influx (measured by myeloperoxidase levels) and IL-6 and TNF concentrations increased equally in D3KO and WT mice, and histological examination of infected mice showed similar pulmonary inflammation in both strains. However, D3KO animals demonstrated significantly higher bacterial load in blood, lung, and spleen compared with WT mice. We conclude that 1) D3 is not required to generate the systemic manifestations of the nonthyroidal illness syndrome in this model; 2) the lack of D3 does not affect the extent of pulmonary inflammation; and 3) bacterial outgrowth in blood, spleen, and lung of D3KO mice is significantly higher than in WT mice. Our results suggest a protective role for D3 in the defense against acute bacterial infection, probably by reinforcing the microbial killing capacity of neutrophils.
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Illness results in increased hypothalamic DIO2 mRNA expression and activity while hypothalamic DIO3 decreases.
“Illness results in increased DIO2 mRNA expression and activity [12, 15–17] while hypothalamic DIO3 decreases [18, 19].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [17]
In “Illness-induced alterations in thyroid hormone metabolism” (page unavailable), the paper reports that D3 mRNA expression and activity decreased during infection in the liver of wild-type mice. It does not report a decrease in hypothalamic D3, the part of the citing sentence to which this source is attached. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA lack of DIO3 impairs the bacterial killing capacity of mice upon infection with Streptococcus pneumonia and increases the mortality of zebrafish embryos with pneumococcal meningitis.
“A lack of DIO3 impairs the bacterial killing capacity of mice upon infection with Streptococcus pneumonia [17] and clearly increases the mortality of zebrafish embryos with pneumococcal meningitis.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [17]
The Bacterial outgrowth section (page unavailable) reports significantly higher bacterial loads in the lungs and spleens of D3-deficient mice after S. pneumoniae infection, supporting impaired clearance. The Abstract and discussion describe reduced microbial killing as a probable explanation, not a directly established result. The zebrafish clause follows the [17] citation and is not attributed to this source. (LLM, conf=0.84)
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Cites
Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data
Ramakers, C. R. B., Ruijter, J. M., Deprez, R. H. L., & Moorman, A. F. M. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01423-4 · Cited by 3,718 · see citing works
Myeloperoxidase: friend and foe
Klebanoff, S. J. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.1204697 · Cited by 2,282 · see citing works
Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.1.0455 · Cited by 1,853 · see citing works
IODINATION OF BACTERIA: A BACTERICIDAL MECHANISM
Klebanoff, S. J. (1967) · The Journal of Experimental Medicine · doi:10.1084/jem.126.6.1063 · Cited by 606 · see citing works
Peeters, R. P., Wouters, P. J., Kaptein, E., van Toor, H., Visser, T. J., & Van den Berghe, G. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-022013 · Cited by 452 · see citing works
Innate immunity and pulmonary host defense
Zhang, P., Summer, W. R., Bagby, G. J., & Nelson, S. (2000) · Immunological Reviews · doi:10.1034/j.1600-065x.2000.917306.x · Cited by 404 · see citing works
Type 3 deiodinase is critical for the maturation and function of the thyroid axis
Hernández, A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26240 · Cited by 344 · see citing works
Alveolar Macrophages Have a Protective Antiinflammatory Role during Murine Pneumococcal Pneumonia
Knapp, S., Leemans, J. C., Florquin, S., Branger, J., Maris, N. A., Pater, J. M., van Rooijen, N., & van der Poll, T. (2003) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200207-698oc · Cited by 302 · see citing works
Knapp, S., Wieland, C. W., Veer, C. V. ′., Takeuchi, O., Akira, S., Florquin, S., & van der Poll, T. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.5.3132 · Cited by 268 · see citing works
Self-citationSweet, M. J., Leung, B. P. L., Kang, D., Søgaard, M., Schulz, K., Trajković, V., Campbell, C., Xu, D., & Liew, F. Y. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.11.6633 · Cited by 248 · see citing works
Alternate Pathways of Thyroid Hormone Metabolism
Wu, S.-Y., Green, W. L., Huang, W.-S., Hays, M. T., & CHOPRA, I. J. (2005) · Thyroid · doi:10.1089/thy.2005.15.943 · Cited by 207 · see citing works
Fliers, E., Guldenaar, S. E. F., Wiersinga, W. M., & Swaab, D. F. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4404 · Cited by 206 · see citing works
Self-citationFekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1439 · Cited by 179 · see citing works
Boelen, A., Kwakkel, J., Thijssen-Timmer, D., Alkemade, A., Fliers, E., & Wiersinga, W. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1820315 · Cited by 159 · see citing works
Self-citationPohlenz, J., MAQUEEM, A., Cua, K., Weiss, R. E., SANDE, J. V., & Refetoff, S. (1999) · Thyroid · doi:10.1089/thy.1999.9.1265 · Cited by 154 · see citing works
Olivares, E. L., Marassi, M. P., Fortunato, R. S., da Silva, A. C. M., Costa-e-Sousa, R. H., Araújo, I. G., Mattos, E. C., Masuda, M. O., Mulcahey, M. A., Huang, S. A., et al. (2007) · Endocrinology · doi:10.1210/en.2007-0043 · Cited by 145 · see citing works
Induction of Thyroid Hormone-Degrading Deiodinase in Cardiac Hypertrophy and Failure
Wassen, F. W. J. S., Schiel, A. E., Kuiper, G. G. J. M., Kaptein, E., Bakker, O., Visser, T. J., & Simonides, W. S. (2002) · Endocrinology · doi:10.1210/endo.143.7.8985 · Cited by 144 · see citing works
Rijneveld, A. W., Florquin, S., Branger, J., Speelman, P., van Deventer, S. J. H., & van der Poll, T. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5240 · Cited by 126 · see citing works
Boelen, A., Kwakkel, J., Alkemade, A., Renckens, R., Kaptein, E., Kuiper, G., Wiersinga, W. M., & Visser, T. J. (2005) · Endocrinology · doi:10.1210/en.2005-0608 · Cited by 117 · see citing works
Self-citationMebis, L., Langouche, L., Visser, T. J., & Van den Berghe, G. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0510 · Cited by 101 · see citing works
Reawakened interest in type III iodothyronine deiodinase in critical illness and injury
Huang, S. A., & Bianco, A. C. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0727 · Cited by 95 · see citing works
Kakucska, I., Romero, L. I., Clark, B. D., Rondeel, J. M. M., Qi, Y., Alex, S., Emerson, C. H., & Lechan, R. M. (2008) · Neuroendocrinology · doi:10.1159/000126649 · Cited by 74 · cited 1× · see citing works
“This phenomenon is observed in both humans and experimental animal models, including rodents (15, 20).”
BackgroundBoelen, A., Boorsma, J., Kwakkel, J., Wieland, C. W., Renckens, R., Visser, T. J., Fliers, E., & Wiersinga, W. M. (2008) · Thyroid · doi:10.1089/thy.2008.0090 · Cited by 70 · see citing works
Self-citationThe Role of Interferon‐γ in Murine Pneumococcal Pneumonia
Rijneveld, A. W., Lauw, F. N., Schultz, M. J., Florquin, S., Velde, A. A. T., Speelman, P., van Deventer, S. J. H., & van der Poll, T. (2002) · The Journal of Infectious Diseases · doi:10.1086/338122 · Cited by 67 · see citing works
Comparative study of pituitary-thyroid hormone economy in fasting and hypothyroid rats.
Germain, D. L. S., & Galton, V. A. (1985) · Journal of Clinical Investigation · doi:10.1172/jci111747 · Cited by 64 · see citing works
Animal Models of Nonthyroidal Disease*
Tibaldi, J. M., & Surks, M. I. (1985) · Endocrine Reviews · doi:10.1210/edrv-6-1-87 · Cited by 58 · see citing works
Pneumonia models and innate immunity to respiratory bacterial pathogens
Knapp, S., Schultz, M. J., & Poll, T. V. D. (2005) · Shock · doi:10.1097/01.shk.0000191385.41689.f3 · Cited by 56 · see citing works
Metabolism of L-Thyroxine by Phagocytosing Human Leukocytes
Woeber, K. A., & Ingbar, S. H. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107361 · Cited by 50 · see citing works
Burger, A., Engler, D., Buergi, U., WEISSEL, M., Steiger, G., Ingbar, S. H., Rosin, R. E., & BABIOR, B. M. (1983) · Journal of Clinical Investigation · doi:10.1172/jci110848 · Cited by 38 · see citing works
Siegel, E. T., & SACHS, B. A. (1964) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-24-4-313 · Cited by 34 · see citing works
Alterations in Thyroid Physiology During Pneumococcal Septicemia in the Rat1
Shambaugh, G. E., & Beisel, W. R. (1966) · Endocrinology · doi:10.1210/endo-79-3-511 · Cited by 27 · see citing works
Adelberg, H. M., Siemsen, J. K., Jung, R. C., & Nicoloff, J. T. (1971) · Radiology · doi:10.1148/99.1.141 · Cited by 21 · see citing works
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Cited by
Sorted by citations
Thyroid function in critically ill patients
Fliers, E., Bianco, A. C., Langouche, L., & Boelen, A. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00225-9 · Cited by 441 · see citing works
Self-citationParadigms of dynamic control of thyroid hormone signaling
Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00275 · Cited by 293 · see citing works
Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection
Boelen, A., Kwakkel, J., & Fliers, E. (2011) · Endocrine Reviews · doi:10.1210/er.2011-0007 · Cited by 287 · see citing works
Self-citationPitfalls in the measurement and interpretation of thyroid function tests
Koulouri, O., Moran, C., Halsall, D., Chatterjee, K., & Gurnell, M. (2013) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2013.10.003 · Cited by 282 · see citing works
Bianco, A. C., Anderson, G., Forrest, D., Galton, V. A., Gereben, B., Kim, B. W., Kopp, P. A., Liao, X. H., Obregon, M. J., Peeters, R. P., et al. (2014) · Thyroid · doi:10.1089/thy.2013.0109 · Cited by 205 · see citing works
An update on non-thyroidal illness syndrome
Fliers, E., & Boelen, A. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01482-4 · Cited by 199 · see citing works
Self-citationThe molecular basis of the non-thyroidal illness syndrome
de Vries, E. M., Fliers, E., & Boelen, A. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0133 · Cited by 192 · see citing works
Self-citationLocal impact of thyroid hormone inactivation
Dentice, M., & Salvatore, D. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0002 · Cited by 143 · see citing works
Thyroid axis function and dysfunction in critical illness
Mebis, L., & Van den Berghe, G. (2011) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.03.002 · Cited by 99 · see citing works
Kwakkel, J., Surovtseva, O. V., de Vries, E. M., Stap, J., Fliers, E., & Boelen, A. (2014) · Endocrinology · doi:10.1210/en.2013-2066 · Cited by 88 · see citing works
Self-citationDifferential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats
de Vries, E. M., van Beeren, H. C., Ackermans, M. T., Kalsbeek, A., Fliers, E., & Boelen, A. (2015) · Journal of Endocrinology · doi:10.1530/joe-14-0533 · Cited by 38 · see citing works
Self-citationvan 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., et al. (2018) · Endocrinology · doi:10.1210/en.2017-00666 · Cited by 33 · see citing works
Self-citationde Vries, E. M., Kwakkel, J., Eggels, L., Kalsbeek, A., Barrett, P., Fliers, E., & Boelen, A. (2014) · Endocrinology · doi:10.1210/en.2013-2018 · Cited by 32 · see citing works
Self-citationvan der Spek, A. H., Bloise, F. F., Tigchelaar, W., Dentice, M., Salvatore, D., van der Wel, N. N., Fliers, E., & Boelen, A. (2016) · Endocrinology · doi:10.1210/en.2016-1103 · Cited by 28 · see citing works
Self-citationMebis, L., Eerdekens, A., Güiza, F., Princen, L., Derde, S., Vanwijngaerden, Y.-M., Vanhorebeek, I., Darras, V. M., Van den Berghe, G., & Langouche, L. (2012) · Endocrinology · doi:10.1210/en.2011-1411 · Cited by 22 · see citing works
Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation
de Vries, E. M., Surovtseva, O., Vos, W. G., Kunst, R. F., van Beeren, M., Kwakkel, J., Chassande, O., Ackermans, M. T., Fliers, E., & Boelen, A. (2019) · Thyroid® · doi:10.1089/thy.2019.0201 · Cited by 16 · see citing works
Self-citation
- Authors
- Boelen, A., Kwakkel, J., Wieland, C. W., St. Germain, D. L., Fliers, E., & Hernandez, A.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Department of Medicine (D.L.S.G., A.H.), Dartmouth Medical School, Lebanon, New Hampshire 03756
- Corresponding author
- Boelen, Anita
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-11-26
- Volume
- 150
- Issue
- 4
- Pages
- 1984-1990
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2659279
- OpenAlex
- W2000322180
- Cited by
- 63
- References
- 32
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 6 · 2018: 1 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 7 · 2013: 3 · 2012: 1
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 054716, R01DK054716, R37DK015070, R01DK015070)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- type 3 deiodinase, Streptococcus pneumoniae, bacterial clearance, acute bacterial infection, low T3 syndrome, thyroid hormones, neutrophils, innate immunity, lung inflammation, bacterial load, interleukin-6, TNF-α, myeloperoxidase
- MeSH terms
- Animals, Female, Iodide Peroxidase, Liver, Lung, Pneumococcal Infections, RNA, Messenger, Spleen, Streptococcus pneumoniae, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine, Interleukin-6, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Mice, Interleukin-1beta
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