Induction of Type 3 Deiodinase Activity in Inflammatory Cells of Mice with Chronic Local Inflammation

Abstract

During illness, changes in thyroid hormone metabolism occur, so-called nonthyroidal illness (NTI). NTI has been characterized by a fall of serum T(3) due to decreased extrathyroidal conversion of T(4) into T(3) by liver type 1 deiodinase (D1), without an increase in serum TSH. Type 3 deiodinase (D3) was thought not to play an important role during NTI, but recently it has been shown that D3 activity is up-regulated in liver and skeletal muscle of critically ill patients related to hypoxia. We studied D3 gene expression and activity in liver and muscle/subcutis of mice during illness, which was induced by two different stimuli: bacterial endotoxin (lipopolysaccharide) administration, resulting in an acute systemic response, and a turpentine injection in each hindlimb, resulting in a local sc abscess. Lipopolysaccharide induced a rapid decrease in liver D1 and D3 activity but not skeletal muscle of hindlimb. In contrast, local inflammation induced by turpentine did not decrease liver D1 and D3 activity but increased markedly D3 activity in the muscle/subcutis sample containing the abscess, associated with strongly increased IL-1beta and IL-6 mRNA expression. Inflammatory cells, surrounding the abscess showed D3 and T(3)-transporter monocarboxylate transporter-8 immunoreactivity, whereas muscle cells did not show any immunoreactivity. In conclusion, local inflammation strongly induces D3 activity in inflammatory cells, especially in invading polymorphonuclear granulocytes, suggesting enhanced local degradation of T(3).

Thyroid hormone metabolism in innate immune cells

“…Murine neutrophils contain the TH transporter MCT8, whereas human neutrophils express MCT10 but not MCT8 mRNA (Boelen et al 2005, van der Spek et al 2016. It has long been known that activated neutrophils are capable of deiodinating both T 3 and T 4 (Woeber 1971, Woeber et al 1972, Klebanoff & Green 1973, Woeber & Ingbar 1973.…”

“…Neutrophils were also shown to contain saturable nuclear-binding sites for T 3 (Woeber 1977). It has since been found that type 3 deiodinase (D3), the TH-inactivating enzyme, is present in both human and murine neutrophils and is located in the cytosol and in bactericidal granules within the cell (Boelen et al 2005, 2008, van der Spek et al 2016. Human neutrophils were also recently shown to express type 1 deiodinase (D1) and TRα1 at the transcriptional level (van der Spek et al 2016).…”

“…Intracellular thyroid hormone metabolism may also play a role in neutrophils during bacterial killing. The thyroid hormone-inactivating type 3 deiodinase (D3) is present in murine and human neutrophils (Boelen et al 2005, 2008, van der Spek et al 2016. Mice that lack this enzyme suffer from impaired bacterial killing (Boelen et al 2009).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…A large number of animal models have been developed to study NTI (361)(362)(363)(364)(365)(366)(367)(368)(369)(370). Essentially, the type and extent of the bodily insult that triggers NTI in rats, mice, and rabbits determines the magnitude of the alterations in thyroid economy.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…In acute inflammation, as in E.Coli-induced peritonitis or in S.Pneumonia-induced pulmonitis, or in a chronic inflammation, as in turpentine-induced muscle abscess, D3 is expressed in tissue infiltrating polymorphonuclear granulocytes under the control of cytokine network (70,71). Since the response to inflammation is, to some extent, impaired in D3KO mice, D3 may have a protective role against acute bacterial infection by enhancing the microbial killing capacity of neutrophils by increasing intracellular iodine (72).…”