Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

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.

Keywords: Wnt/β-catenin; human immunodeficiency virus; hypothalamic–pituitary–thyroid; immune system; inflammasome; microRNAs; non-thyroidal illness syndrome; thyroid hormones.

FIGURE 1

Regulation of NLRP3 inflammasome by thyroid hormones in macrophages. Physiological levels of T₃ promote anti-inflammatory responses, bactericidal activity, and phagocytosis (left panel). Mechanistically, T₃–THRs–TREs complex downregulates TLR4, NF-kB, NLRP3, pro-IL-1β, pro-IL-18, and several miRNAs, such as miR-31, -155, and -222, thus reducing ROS levels. Moreover, the T₃–THRs–TREs complex upregulates miR-30, -133, and -144 that target Fasl, Ilk, Serpine1, hepatocyte growth factor (Hgf), Beta secretase 1 (Bace 1), and C-X-C motif chemokine receptor 4 (Cxcr4), thus further preventing the assembly of NLRP3 inflammasome (Forini et al., 2019). Hypothyroidism induces acute and chronic inflammatory responses, such as NTIS (right panel). High levels of T₄ cause a robust production of ROS through the integrin αvβ3–PI3K–AKT signaling cascade, which ultimately triggers NLRP3 inflammasome. This is due to higher affinity displayed by T₄ then T₃ for integrin αvβ3 receptor on cell membrane. In addition, the T₄–integrin αvβ3–MAPKs axis enhances the expression of HIF-1α and COX2 to promote NLRP3 inflammasome assembly and stability.

FIGURE 2

Thyroid hormones, Wnt pathway, and miRNAs crosstalk. (A) The T₃–THRs–TREs complex upregulates DKK4, a tumor suppressor, which inhibits Wnt/β-catenin pathway. (B) Also, the T₃–THRs–TREs complex increases miR-499 and downregulates calcineurin and miR208a, thus reducing apoptosis, cardiac hypertrophy, inflammation, and NTIS.