Category: Autoimmune neurologic diseases
Thyroid hormone-thyroid hormone receptor beta (TRβ) signaing is widely accepted as an orchestrator of lipid metabolism in our body, however its role in immune system is rarely known. Here we report a novel insight of TRβ signaling in immune system. Thrb gene is highly expressed in CNS-infiltrating CD4 T cells during the development of experimental encephalomyelitis (EAE). Silencing of TRβ ameliorated the severity of EAE with the reduction of the transcriptional levels of IL-17 in encephalitogenic CD4 T cells. On the other hand, the administration of sobetirome, the selective TRβ agonist, exacerbated the disease course of EAE with the reduction of IL-10 in encephalitogenic CD4 T cells and promoted in vitro Th17 differentiation of naïve CD4 T cells in the presence of IL-1β. Intracellular staining of TRβ revealed the expression of TRβ in Th17 cells and the silencing of TRβ reduced the IL-17 production in vitro, indicating a T cell-intrinsic role of TRβ. In addition, sobetirome increased glycolytic and lipogenic genes of hypoxia-inducible factor-1α (HIF-1α) and acetyl-CoA carboxylase-1 (ACC-1) during Th17 differentiation. And a chemical inhibition of de novo lipogenesis completely restrained Th17 skewing via sobetirome, suggesting the possible involvement of de novo lipogenesis through TRβ signaling. Finally, TGF-β1-induced IL-10 productions in naïve CD4 T cells were severely reduced in the presence of sobetirome. Taken together, we propose a novel mechanism for modulation of IL-17/IL10 balance via TRβ signaling as an example of active cross-talk between immune and endocrine systems.
Yoshimitsu Doi– National Institute of Neuroscience, National Center of Neurology and Psychiatry