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Abstract
Thyroid hormones have immunomodulatory roles, but their effects on the transcriptome and epigenome of innate immune cell types remain unexplored. In this study, we investigate the effects of triiodothyronine (T3) on the transcriptome and methylome of human monocytes in vitro, both in resting and lipopolysaccharide (LPS)-stimulated conditions. In resting monocytes, 5 µM T3 affected the expression of a small number of monocyte-to-macrophage differentiation-associated genes, including TLR4 (p-value < 0.05, expression fold change >1.5). T3 attenuated a small proportion of monocyte-to-macrophage differentiation-associated DNA methylation changes, while specifically inducing DNA methylation changes at several hundred differentially methylated CpG probes (DMPs) (p-value < 0.05, Δβ > 0.05). In LPS-stimulated monocytes, the presence of T3 attenuated the effect of 27% of LPS-induced DMPs (p-value < 0.05, Δβ > 0.05). Interestingly, co-stimulation with T3 + LPS induced a unique DNA methylation signature that was not observed in the LPS-only or T3-only exposure groups. Our results suggest that T3 induces limited transcriptional and DNA methylation remodeling in genes enriched in metabolism and immune processes and alters the normal in vitro LPS response. The overlap between differentially expressed genes and genes associated with DMPs was minimal; thus, other epigenetic mechanisms may underpin the expression changes. This research provides insight into the complex interplay between thyroid hormones, epigenetic remodeling, and transcriptional dynamics in monocytes.
Highlights
Cells of the innate immune system, primarily monocytes, can form nonspecific memory in response to a range of microbial compounds, danger signals, and metabolic precursors [1,2]
Monocytes were cultured for 24 h in RPMI medium alone or with 5 μM T3, and molecular profiling was performed at attachment (0 h; RNA and DNAme), 4 h (RNA), and 24 h (RNA and DNAme) (Figure 1A)
We identified the 40 differentiation-associated Differentially expressed genes (DEGs) attenuated by T3 (Figure 1C, Table S1), including toll-like receptor 4 (TLR4), which was upregulated by T3 at both time points (Figure 1D, Table S1)
Summary
Cells of the innate immune system, primarily monocytes, can form nonspecific memory in response to a range of microbial compounds, danger signals, and metabolic precursors [1,2]. This memory, known as trained immunity, is underlined by metabolic, epigenetic, and transcriptional reprogramming [3–5]. There has been a strong focus on reproductive hormones and glucocorticoids, but in recent years, thyroid hormones have been proposed to have an immunomodulatory role [10–16]. This has been highlighted in studies of murine macrophages in the context of response to lipopolysaccharide (LPS) [10,11]
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