Endocrine Abstracts

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. Cellular TH concentrations are, in part, determined by TH transporters, cellular gateways facilitating bidirectional TH transport. An important TH transporter family is the monocarboxylate transporters (MCT) family including Mct8 and Mct10. To investigate the contribution of Mct8 and Mct10 in macrophage function, we used bone marrow derived macrophages (BMDM) from mice lacking Mct8 (Mct8ko), Mct10 (Mct10ko), or both (Mct8/10dko). Isolated BMDM from wild type (WT) and knockout mice were then polarized into M1 or M2 cells using LPS + interferon gamma or IL-4 respectively. To determine the intracellular TH availability in BMDM, mRNA expression of TH responsive genes was measured in the cells of wild type (WT) and knockout mice. Macrophage phenotype was assessed by measuring cell surface marker expression using flow cytometry, and secretion and expression of pro-inflammatory (TNFα and IL-1β) and immunomodulatory (IL-10) cytokines. T3 responsive gene expression was unchanged in unpolarised Mct8KO and Mct10KO BMDM vs WT BMDM. In Mct8/10dKO cells T3 responsive gene expression was decreased, suggesting that only when both transporters are absent intracellular T3 availability decreases. After polarization into M1 macrophages, Mct8ko macrophages showed increased secretion of TNFα, and increased IL-1β gene expression compared to WT M1 cells, suggesting an increased pro-inflammatory profile. Mct10KO M1 cells were unchanged compared to WT M1 cells. In Mct8/10dko M1 macrophages, CD86 (an M1 surface marker) was increased compared to WT M1 cells, while TNFα secretion was increased as well. After polarization into M2 macrophages, both Mct10ko and Mct8/10dKO macrophages demonstrated increased IL-10 expression while M2-surfacemarkers were unaltered compared to WT M2 cells. In conclusion, only the absence of both Mct8 and Mct10 reduces intracellular TH availability. Pro-inflammatory macrophage phenotype is enhanced in both Mct8KO and Mct8/10dKO M1 macrophages compared to WT, whereas both Mct10 and Mct8/10dKO M2 BMDM show increased anti-inflammatory cytokine secretion compared to M2 WT cells. This suggests that these effects may be at least partially due to other functions of the Mct8 and Mct10 transporters and not solely a T3 effect. These results provide new insights in the complicated interplay between TH and the immune system. It also emphasizes the importance of future research, as clinical implications are unknown and remain to be elucidated.