Thyroid Hormone, Thyroid Hormone Metabolites and Mast Cells: A Less Explored Issue

Abstract

Mast cells are primary players in immune and inflammatory diseases. In the brain, mast cells are located at the brain side of the blood brain barrier (BBB) exerting a crucial role in protecting the brain from xenobiotic invasion. Furthermore, recent advances in neuroscience indicate mast cells may play an important role in glial cell-neuron communication through the release of mediators, including histamine. Interestingly, brain mast cells contain not only 50% of the brain histamine but also hormones, proteases and lipids or amine mediators; and cell degranulation may be triggered by different stimuli activating membrane bound receptors including the four types of histaminergic receptors. Among hormones, mast cells can store thyroid hormone (T3) and express membrane-bound thyroid stimulating hormone receptors (TSHRs), thus suggesting from one side that thyroid function may affect mast cells function, from the other that mast cell degranulation may impact on thyroid function. In this respect, the research on hormones in mast cells is scarce. Recent pharmacological evidence indicates the existence of a non-genomic portion of the thyroid secretion including thyroid hormone metabolites. Among which the 3,5 diiodothyronine (3,5-T2), 3-iodothyroanamine (T1AM) and 3-iodothyroacetic acid (TA1) are the most studied. All these compounds are endogenously occurring and found to be increased in inflammatory-based diseases involving mast cells. T1AM and TA1 induce, as T3, neuroprotective effects and itch but also hyperalgesia in rodents with a mechanism largely unknown but mediated by the release of histamine. Due to the rapid onset of their effectiveness they may trigger histamine release from a cell where it is “ready-to-be released,” i.e., mast cells. Following a very thin path which passes through old experimental and clinical evidence, at the light of novel acquisitions on endogenous T3 metabolites, we aim to stimulate the attention on the possibility that mast cell histamine may be the connector of a novel (neuro) endocrine pathway linking the thyroid with mast cells.

Brain Histamine Modulates the Antidepressant-Like Effect of the 3-Iodothyroacetic Acid (TA1)

“…Our data suggest that histamine may derive, at least in part, from brain mast cells. The observation that TA1 triggers histamine release from mast cells opens the way to the existence of a novel and not-yet-explored relationship between thyroid endocrine components, anxiety like behaviors and the immune system (Landucci et al, 2019). In addition, since mast cells are ubiquitous cells, the degranulating capacity of TA1 has to be taken into consideration when the pharmacological effects of TA1 are investigated.…”

Mast cell quantification in the skin of dogs with hormonal dermatosis

“…T3 is co-stored with histamine in mast cell granules or is degraded to 3iodothyronamine (T1AM) and/or 3iodothyroacetic acid (TA1). T1AM and TA1 derived from circulation or produced inside mast cells trigger mast cell degranulation releasing T3 and histamine which mediates pain, itch and central effects including neuroprotection/neuroinflammation (Landucci et al, 2019).…”

Administration and Pharmacokinetics of Levothyroxine

“…3-iodothyroacetic acid. The biological activity of metabolites of LT4 remains to be established; 3-iodothyroacetic acid, for example, has been shown to induce antidepressant effects, and to promote itching and discomfort, in animal models [21]. [16,17] The elimination half-life of LT4 after oral dosing averages 7.5 days in patients with hypothyroidism, consistent with once-daily dosing [14].…”

“…Polymorphisms of deiodinases may inhibit the conversion of LT4 to T3 in the periphery and have been proposed to explain an incomplete effect of exogenous LT4 treatment in resolving symptoms of hypothyroidism in some patients [18]. Multiple metabolites of thyroid hormones exist, and some of these may have intriguing biological actions that are the focus of current research [19][20][21]. Pathways for biotransformation of LT4 include decarboxylation and oxidative deamination, which results in, e.g.…”