Endocrine Abstracts

Thyroid hormones (TH) stimulate the growth of microglia cellular processes, which are reduced in hypothyroid and increased in hyperthyroid pups. However, how TH triggers its effects on these cells remains unexplored. Using confocal immunofluorescence, we have found that in the brains of postnatal day (P)5 mice, infiltrating microglia with a motile ameboid phenotype (lectin tomato and iba1 positive) exhibit strong staining of the inactivating deiodinase type 3 (D3). However, when microglia cells enter the cerebral cortex and differentiate into a sessile ramified phenotype, microglial cells did not express D3 anymore. Culture ameboid microglia (cd11b+) obtained from the brains of P5 mice express D3 at the protein and mRNA level (by RT-PCR). These exciting observations point to a new local control of TH signaling in infiltrating microglial cells, and more investigations are ongoing. We have set up a system that allows us to isolate infiltrating cd11b+ microglia from the subcortical white matter of P5 mice brains using specific microbeads. We will study the transcriptome of these cells using bulk RNA-seq and compare it to cd11b+ microglial cells obtained from P5 pups treated from P1 to P5 with either xanthohumol or triiodothyronine (T3). Next, we will isolate microglia from the transgenic thyroid hormone action indicator mouse and treat them with ATP and LPS (to promote migration or differentiation, respectively). In these cells, we will measure Dio3 mRNA levels together with luciferase (the readout of TH signaling in these mice). The involvement of the TH cell membrane transporter MCT8, is being studied using (i) super-resolution microscopy and (ii) brain organoids (wildtype and MCT8-deficient) containing microglial cells. The discovery that D3 and MCT8 are at the crossroads of the local control of TH signaling in infiltrating microglia has enormous potential for many neurodegenerative diseases and cannot be underestimated.