Abstract
The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.
Highlights
Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) produced by the hypothalamus and pituitary gland, respectively, are effectors of the hypothalamic–pituitary– thyroid (HPT) axis, which regulates levels of circulating thyroid hormones (THs; Kelly, 2000)
We have discussed the bilateral crosstalk between the immune system and THs both in physiological and patho-physiological conditions
The activation of Nod-like receptor protein 3 (NLRP3) inflammasome, modulation of the Wnt/β-catenin pathway, and non-thyroidal illness syndrome (NTIS) could rely on a complex interplay that involves THs and miRNAs
Summary
Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) produced by the hypothalamus and pituitary gland, respectively, are effectors of the hypothalamic–pituitary– thyroid (HPT) axis, which regulates levels of circulating thyroid hormones (THs; Kelly, 2000). The T3–THRs–TREs complex downregulates the TLR4/NF-kB pathway (Furuya et al, 2017; de Castro et al, 2018), reducing the levels of NLRP3, pro-IL-1β, and pro-IL-18 All this suggests that T3–THRs nuclear action may direct immune cells to an anti-inflammatory condition (Vargas and Videla, 2017; Forini et al, 2019; Figure 1, left panel). MiR-499 related to cardioprotection (Wang et al, 2011) inhibits calcineurin (a signaling molecule of Wnt/β-catenin pathway), reducing the levels of Dynamin1-like protein (Drp1), which is involved in apoptosis (Tan et al, 2008) Another cardiac-specific miRNA (Seok et al, 2014; Wang et al, 2015; Su et al, 2016), miR-208a, inhibits T3mediated signaling pathway by repressing the THs Associated Protein/Mediator Complex Subunit 13 (THRAP1/MED13) in a mouse model of cardiac hypertrophy and hypothyroidism (van Rooij et al, 2009; Neppl and Wang, 2014; Figure 2B). There is ample evidence about the THs/THRs/miRNAs alterations in immune-related pathologies, it will be crucial to further explore the regulatory networks between miRNAs and THs in pathological contexts such as NTIS
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