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T1AM/TAAR1 System Reduces Inflammatory Response and β-Amyloid Toxicity in Human Microglial HMC3 Cell Line
Beatrice Polini1, Caterina Ricardi1, Andrea Bertolini1
1Department of Pathology, University of Pisa, 56100 Pisa, Italy.
Abstract:
Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). 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. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM's effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or β-amyloid peptide 25-35 (Aβ25-35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediated inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1, and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells turned out to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDDs.
Insights
3-iodothyronamine (T1AM) reduces neuroinflammation by inhibiting microglial activation. This thyroid hormone derivative, acting via trace amine-associated receptor 1 (TAAR1), offers a potential therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial dysfunction and neuroinflammation are central to neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's.
- Aberrant protein aggregation in NDDs activates microglia, exacerbating neuroinflammation and oxidative stress.
- Targeting glial activation presents a potential therapeutic avenue for neurodegeneration.
Purpose of the Study:
- To investigate the effects of 3-iodothyronamine (T1AM) on microglial inflammatory responses.
- To determine if T1AM can inhibit inflammation induced by lipopolysaccharide/tumor necrosis factor-alpha (LPS/TNFα) or beta-amyloid peptide 25-35 (Aβ25-35) in human microglial cells.
- To elucidate the role of trace amine-associated receptor 1 (TAAR1) in T1AM's anti-inflammatory actions.
Main Methods:
- Utilized human HMC3 microglial cell line.
- Stimulated cells with LPS/TNFα or Aβ25-35 peptide.
- Assessed inflammatory mediator levels using ELISA and qPCR assays.
Main Results:
- T1AM significantly inhibited the release of pro-inflammatory factors (IL-6, TNFα, NF-kB, MCP1, MIP1) in response to stimuli.
- T1AM promoted the release of the anti-inflammatory mediator IL-10.
- The observed anti-inflammatory effects of T1AM were confirmed to be mediated by TAAR1.
Conclusions:
- T1AM demonstrates potent anti-inflammatory effects on activated human microglial cells.
- The T1AM/TAAR1 system represents a promising therapeutic target for managing neuroinflammation in neurodegenerative diseases.
- Further research into T1AM's neuroprotective mechanisms in NDDs is warranted.
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