Endocrine Abstracts

Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha (RTHα) is a syndrome whose features include delayed growth and neurocognitive development. Macrophages, which derive from circulating monocytes and have recently been recognized as important thyroid hormone target cells, are innate immune cells that are capable of adopting a wide range of phenotypes. Assuming the right phenotype in the right setting is crucial as macrophage dysfunction has been linked to a broad spectrum of diseases including cancer and diabetes. Knockdown of thyroid hormone receptor alpha (TRα) results in impaired macrophage function in murine and in vitro models, suggesting that T3 signalling via the TRα is a key regulator of macrophage function. The aim of this study is to assess monocyte and macrophage in patients with a severe form of RTHα. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) derived from 7 RTHα patients and 7 healthy controls. Monocytes were phenotyped using cell surface marker expression and differentiated into macrophages in vitro. Monocyte-derived macrophages were treated with lipopolysaccharide (LPS) to induce a pro-inflammatory phenotype, IL-4 to induce an immunomodulatory phenotype or solvent control. Macrophage phenotype was measured using cell surface marker expression and cytokine secretion. Finally, fresh whole blood from RTHα patients and healthy controls was treated with LPS, after which cytokine secretion was quantified as a measure for whole blood pro-inflammatory response. RTHα patients show changes in circulating monocyte subtypes, with a lower percentage of classical monocytes and increased intermediate and non-classical monocytes compared to healthy controls. Increased intermediate monocytes are associated with cardiovascular and autoimmune disease. Monocyte-derived macrophages from RTHα patients exhibit an impaired response to pro-inflammatory stimuli characterized by reduced expression of CD80 and reduced secretion of TNFα after LPS compared to healthy control macrophages. RTHα macrophages polarized into an immunomodulatory phenotype demonstrate decreased secretion of the immunomodulatory cytokines TGF-β and IL-17a compared to cells from healthy controls, suggesting an impaired ability to generate a pro-inflammatory Th17 adaptive immune response. Interestingly, LPS-treated whole blood from RTHα patients also showed a significantly lower concentration of IL-17a than in healthy controls. In conclusion, monocytes and macrophages derived from RTHα patients exhibit changes in phenotype and response to inflammatory and anti-inflammatory stimuli. This novel human data demonstrates an important role for T3 signaling via the TRα in both the pro-inflammatory response of the innate immune system and the shaping of the subsequent adaptive immune response.