Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) profiles. Previous studies have established that increased TH concentrations shift macrophages into a more pro-inflammatory phenotype. The active thyroid hormone triiodothyronine (T3) exerts its action through the nuclear thyroid hormone receptor (TR), of which the TRα is the predominant receptor in macrophages. The role of the TRα in macrophage polarization is not completely understood.
The role of the TRα in macrophage function was investigated using bone marrow derived macrophages (BMDMs) from transgenic mice with either a knockout of the TRα (TRαKO), a mutation in the DNA binding domain (TRαGS, thereby impairing canonical genomic action via the TRα), or a mutation in the T3 binding domain of the TRα (TRαPV, a dominant negative variant, resulting in resistance to thyroid hormone). BMDMs from these mice and corresponding wild types (WT) were polarized into a pro-inflammatory M1 or immunomodulatory M2 phenotype using either LPS + interferon gamma or IL-4 respectively. Pro- and anti-inflammatory cell surface marker expression was measured with flow cytometry.
After polarization into an M1 phenotype, expression of the M1 surface marker CD80 decreased in TRαPV macrophages, indicating a decreased pro-inflammatory profile. The M2 cell surface marker CD206 did not change in TRαPV M2 macrophages compared to WT, while this marker increased in M2 polarized TRαGS and TRαKO macrophages, which suggests an increased immunomodulatory profile.
In conclusion, a dominant negative mutation of the TRα results in decreased pro-inflammatory marker expression in M1 cells whereas a lack of canonical TRα signaling increases anti-inflammatory cell surface marker expression in M2 cells. These results suggest that canonical T3 signaling via the TRα is important for the determination of macrophage function, with a lack of T3-TRα signaling resulting in a more immunomodulatory phenotype.