Regulation of Microglial Development: A Novel Role for Thyroid Hormone

Abstract

The postnatal development of rat microglia is marked by an important increase in the number of microglial cells and the growth of their ramified processes. We studied the role of thyroid hormone in microglial development. The distribution and morphology of microglial cells stained with isolectin B4 or monoclonal antibody ED1 were analyzed in cortical and subcortical forebrain regions of developing rats rendered hypothyroid by prenatal and postnatal treatment with methyl-thiouracil. Microglial processes were markedly less abundant in hypothyroid pups than in age-matched normal animals, from postnatal day 4 up to the end of the third postnatal week of life. A delay in process extension and a decrease in the density of microglial cell bodies, as shown by cell counts in the developing cingulate cortex of normal and hypothyroid animals, were responsible for these differences. Conversely, neonatal rat hyperthyroidism, induced by daily injections of 3,5,3Ј-triiodothyronine (T3), accelerated the extension of microglial processes and increased the density of cortical microglial cell bodies above physiological levels during the first postnatal week of life.Reverse transcription-PCR and immunological analyses indicated that cultured cortical ameboid microglial cells expressed the ␣1 and ␤1 isoforms of nuclear thyroid hormone receptors. Consistent with the trophic and morphogenetic effects of thyroid hormone observed in situ, T3 favored the survival of cultured purified microglial cells and the growth of their processes. These results demonstrate that thyroid hormone promotes the growth and morphological differentiation of microglia during development.

A model of the development of the brain as a construct of the thyroid system.

“…Microglial cells express the TRα1 and TRβ1 isoforms and are influenced by thyroid hormone (86). Microglial cell density and process formation are depressed in the parietal cortex of neonatal rats exposed to hypothyroid conditions from GD16 through lactation (86). In contrast, hyperthyroidism induced by T 3 injections to euthyroid and prenatally hypothyroid rat pups increased microglial cell survival and branching of the developing axonal fiber tracts of the corpus callosum.…”

“…A deficiency of GFAP during development inhibits the branching necessary for astrocyte-neuronal connections and decreases the long-term potentiation capacity, a factor essential to learning and memory (85). Microglial cells express the TRα1 and TRβ1 isoforms and are influenced by thyroid hormone (86). Microglial cell density and process formation are depressed in the parietal cortex of neonatal rats exposed to hypothyroid conditions from GD16 through lactation (86).…”

Thyroid hormone metabolism in innate immune cells

“…Both murine and human microglia express high levels of LAT2 in addition to MCT10 and OATP4a1, allowing them to transport TH into the cell (Wirth et al 2009, Braun et al 2011. In addition, microglia express both TRα 1 and TRβ 1 (Lima et al 2001). Physiological TH concentrations appear to be crucial for microglial growth and morphological differentiation (Lima et al 2001).…”

“…In addition, microglia express both TRα 1 and TRβ 1 (Lima et al 2001). Physiological TH concentrations appear to be crucial for microglial growth and morphological differentiation (Lima et al 2001). Hypothyroid rats showed delayed microglial growth and differentiation, whereas hyperthyroid animals displayed the opposite phenotype with accelerated microglial growth and differentiation (Lima et al 2001).…”

“…Physiological TH concentrations appear to be crucial for microglial growth and morphological differentiation (Lima et al 2001). Hypothyroid rats showed delayed microglial growth and differentiation, whereas hyperthyroid animals displayed the opposite phenotype with accelerated microglial growth and differentiation (Lima et al 2001). A recent study by Mori and coworkers assessed in detail the effects of T 3 on microglial activation and the signalling pathways involved (Mori et al 2015).…”