Endocrine Abstracts

Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDD), including Alzheimer’s disease (AD), Parkinson’s disease (AD), and amyotrophic lateral sclerosis (ALS). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. The availability of cell-permeable inhibitors of glial activation and neuroinflammation could represent a valid tool for the treatment or prevention of common NDD. Recently, 3-iodothyronamine (T1AM), an endogenous amine putatively derived from thyroid hormone (TH) metabolism, gained interest for its ability to promote neuroprotective effects in several models, including seizure-related excitotoxic damage, altered autophagy, amyloidosis and OGD-induced synaptic dysfunction. Nevertheless, T1AM’s effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could decrease the inflammatory phenotype (M1) of LPS/TNFα-stimulated human microglial cells (HMC3), promoting the transition to the protective M2 phenotype. Dose-response experiments, carried out by exposing HMC3 cells to pretreatment with increasing concentrations (0.1, 1, and 10 μM) of T1AM followed by LPS/TNFα treatment, revealed that T1AM causes a significant (P < 0.05) dose-dependent reduction of pro-inflammatory interleukin-6 (IL-6) secretion as compared to LPS/TNFα treated cells. A significant dose-dependent increase of anti-inflammatory interleukin-10 (IL-10) was also observed. Expression of TAAR1, T1AM’s putative receptor, in HMC3 cells was also assessed by qPCR analysis, and no changes were observed after 24 h treatment with LPS/TNFα. Notably, TAAR1 was demonstrated to be a chief target of T1AM anti-inflammatory action in HMC3 cells. Indeed, we observed that T1AM protective effect against microglia-activation was abolished by co-administration of TAAR1 selective antagonist EPPTB (5 nM). Conversely, administration of TAAR1 agonist RO5166017 (1 μM) produced a reduction of pro-inflammatory IL-6 comparable to that previously observed after administering T1AM (1 μM). Since 3-iodothyroacetic acid (TA1), the major catabolite of T1AM, has been reported to be responsible for some effects elicited by T1AM treatment, we checked whether TA1 administration could also decrease the inflammatory phenotype of LPS/TNFα-stimulated HMC3 cells. We observed that TA1 administered at 0.1, 1, and 10 μM concentrations was not able to produce any significant effect on both IL-6 and IL-10 release from LPS/TNFα-stimulated HMC3 cells, suggesting that the induction of microglial transition from pro-inflammatory to anti-inflammatory phenotype is exclusively due to the action of T1AM through the interaction with the TAAR1 receptor.