Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function

Abstract

Innate immune cells, including macrophages, have recently been identified as target cells for thyroid hormone. We hypothesized that optimal intracellular concentrations of the active thyroid hormone triiodothyronine (T3) are essential for proinflammatory macrophage function. T3 is generated intracellularly by type 2 deiodinase (D2) and acts via the nuclear thyroid hormone receptor (TR). In zebrafish embryos, D2 knockdown increased mortality during pneumococcal meningitis. Primary murine D2 knockout macrophages exhibited impaired phagocytosis and partially reduced cytokine response to stimulation with bacterial endotoxin. These effects are presumably due to reduced intracellular T3 availability. Knockdown of the main TR in macrophages, TRa, impaired polarization into proinflammatory macrophages and amplified polarization into immunomodulatory macrophages. Intracellular T3 availability and action appear to play a crucial role in macrophage function. Our data suggest that low intracellular T3 action has an antiinflammatory effect, possibly due to an effect on macrophage polarization mediated via the TRa. This study provides important insights into the link between the endocrine and innate immune system. (Endocrinology 159: 2241-2252, 2018) T hyroid hormones (THs) are essential for growth, development, and energy metabolism (1). Innate immune cells have recently been identified as TH target cells [for review, see van der Spek et al. (2)]. Macrophages are important innate immune cells that play essential roles in tissue homeostasis and immunity. Macrophage dysfunction has been linked to a large number of pathophysiological conditions, including cancer, diabetes, inflammatory bowel disease, and atherosclerosis (3).