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The Role of Thyroid Hormone in the Innate and Adaptive Immune Response during Infection

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Abstract

In the past decades, there has been growing evidence for a functional interaction between the thyroid hormone and the immune system. This article provides an overview of the mechanisms by which thyroid hormones affect the innate and adaptive immune response during infection.

The influence of thyroid hormone on the most important players of the innate [neutrophils, macrophages, natural killer (NK) cells, and dendritic cells (DCs)] and adaptive immune system (B‐ and T‐lymphocytes) is reviewed here based on both clinical and preclinical studies. The effects of modulation of the immune system by drugs, such as monoclonal antibodies, tyrosine kinase inhibitors, and interferons on thyroid function, are beyond the scope of this article.

Thyroid hormones regulate the activity of neutrophils which is reflected by higher numbers of neutrophils outside the bloodstream and enhanced activity of the respiratory burst following stimulation with thyroid hormone. Hyperthyroidism affects neutrophil function to a larger extent than hypothyroidism. In addition to neutrophil function, macrophage function is strongly affected by thyroid hormones, with triiodothyronine having a pro‐inflammatory effect in these cells. NK cell proliferation and cytotoxic activity are also dependent on thyroid hormone levels. Finally, thyroid hormones enhance DC proliferation and maturation.

In the adaptive immune system, a hyperthyroid state leads to increased activation of lymphocytes. This effect of thyroid hormone is mediated by various factors including NF‐κB and protein kinase C signaling pathways and the β‐adrenergic receptor.

In general, a hyperthyroid state leads to a more activated immune system whereas hypothyroidism leads to a less activated immune system. © 2020 American Physiological Society. Compr Physiol 10:1277‐1287, 2020.

Figure 1. Figure 1. Here the structure of the different thyroid hormones is illustrated. T4 consists of four iodine atoms, whereas T3 only has three iodine atoms, missing one iodine atom on the outer ring.
Figure 2. Figure 2. A schematic overview of the hypothalamus–pituitary–thyroid axis (HTP axis). Thyrotropin‐releasing hormone (TRH) is released by the hypothalamus and stimulates the pituitary gland to release thyroid‐stimulating hormone (TSH). TSH, in turn, stimulates the thyroid gland to produce thyroid hormones T4 and T3. Via a negative feedback loop, T3 and T4 suppress the release of TRH and TSH by the hypothalamus and pituitary gland, respectively.
Figure 3. Figure 3. Cellular thyroid hormone metabolism: The most important thyroid hormone transporters are MCT8 and MCT10, and LAT2. Once in the cytoplasm either deiodinase 3 (D3) transforms T4 into rT3 or deiodinase 1 or 2 (D1 or D2) transform T4 into T3. T3 enters the cell nucleus and binds to a specific region on the DNA, enabling a specific DNA region to be transcribed.
Figure 4. Figure 4. D2 knockdown impairs zebrafish survival during bacterial meningitis. (A) Kaplan–Meier survival curve of zebrafish embryos pretreated with D2 morpholino (D2MO) or scrambled control morpholino (SCMO) during bacterial meningitis induced by injection of 500 CFU of S. pneumoniae into the hindbrain ventricle. (B) Kaplan–Meier survival curve of zebrafish embryos pretreated with D2MO or SCMO or D2MO and T3 during bacterial meningitis. Data represent 40 embryos per group. P‐value for log rank (Mantel‐Cox) test is indicated. Reused, with permission, from van der Spek AH, et al., 2018 84.
Figure 5. Figure 5. NK cell proliferation in the spleen is enhanced by thyroxine. The total number (mean ± SE) of NK cells in the bone marrow and spleen of control (vehicle‐injected; □) and thyroxin‐treated (▪) 6‐month‐old female (A) and male (B) DBA/2 mice. Number of mice is given in parentheses. Reused, with permission, from Mahoney MX, et al., 1998 49.


Figure 1. Here the structure of the different thyroid hormones is illustrated. T4 consists of four iodine atoms, whereas T3 only has three iodine atoms, missing one iodine atom on the outer ring.


Figure 2. A schematic overview of the hypothalamus–pituitary–thyroid axis (HTP axis). Thyrotropin‐releasing hormone (TRH) is released by the hypothalamus and stimulates the pituitary gland to release thyroid‐stimulating hormone (TSH). TSH, in turn, stimulates the thyroid gland to produce thyroid hormones T4 and T3. Via a negative feedback loop, T3 and T4 suppress the release of TRH and TSH by the hypothalamus and pituitary gland, respectively.


Figure 3. Cellular thyroid hormone metabolism: The most important thyroid hormone transporters are MCT8 and MCT10, and LAT2. Once in the cytoplasm either deiodinase 3 (D3) transforms T4 into rT3 or deiodinase 1 or 2 (D1 or D2) transform T4 into T3. T3 enters the cell nucleus and binds to a specific region on the DNA, enabling a specific DNA region to be transcribed.


Figure 4. D2 knockdown impairs zebrafish survival during bacterial meningitis. (A) Kaplan–Meier survival curve of zebrafish embryos pretreated with D2 morpholino (D2MO) or scrambled control morpholino (SCMO) during bacterial meningitis induced by injection of 500 CFU of S. pneumoniae into the hindbrain ventricle. (B) Kaplan–Meier survival curve of zebrafish embryos pretreated with D2MO or SCMO or D2MO and T3 during bacterial meningitis. Data represent 40 embryos per group. P‐value for log rank (Mantel‐Cox) test is indicated. Reused, with permission, from van der Spek AH, et al., 2018 84.


Figure 5. NK cell proliferation in the spleen is enhanced by thyroxine. The total number (mean ± SE) of NK cells in the bone marrow and spleen of control (vehicle‐injected; □) and thyroxin‐treated (▪) 6‐month‐old female (A) and male (B) DBA/2 mice. Number of mice is given in parentheses. Reused, with permission, from Mahoney MX, et al., 1998 49.
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Julia Rubingh, Anne van der Spek, Eric Fliers, Anita Boelen. The Role of Thyroid Hormone in the Innate and Adaptive Immune Response during Infection. Compr Physiol 2020, 10: 1277-1287. doi: 10.1002/cphy.c200003