Diminished pro-inflammatory characteristics in murine bone marrow derived macrophages with impaired thyroid hormone receptor alpha signaling

Macrophages are versatile phagocytes of the innate immune system with functions ranging from pro-inflammatory to immunomodulatory. Macrophages are receptive to signals from thyroid hormones (THs). Here, we studied the role of the TH receptor (TR)α1 in macrophage function. Using wild type and transgenic mice with a mutation in the T3 binding domain of the TRα1 (TRα1PV), we generated bone marrow derived macrophages (BMDMs) and subsequently polarized them into pro-inflammatory or immunomodulatory phenotypes. The phenotype and function of the unpolarized, pro-inflammatory and immunomodulatory TRα1PV BMDMs was compared to the respective wild type BMDMs. The pro-inflammatory TRα1PV BMDMs displayed decreased pro-inflammatory markers, while marker expression of unpolarized and immunomodulatory TRα1PV BMDMs was unaltered. Glycolysis, a characteristic of proinflammatory macrophages, was reduced in all three TRα1PV macrophage phenotypes. Moreover, RNA sequencing revealed different expression profiles and alterations of biological pathways, including immune functions in all TRα1PV BMDMs phenotypes. Altogether, we observed that the TRα1PV mutation results in phenotypical and functional different BMDMs, with most striking changes in the pro-inflammatory phenotype, underlining the significance of adequate T3-TRα1 signaling in pro-inflammatory macrophage responses.