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Inflammatory changes in peripheral organs in the BACHD murine model of Huntington's disease
Priscila Aparecida Costa Valadão1, Bruna da Silva Oliveira1, Julliane V Joviano-Santos1
1Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Insights
Huntington's disease (HD) models show altered immune responses in peripheral organs. This study reveals significant changes in inflammatory cytokine levels in the kidneys, heart, liver, and spleen of BACHD mice, suggesting a role for peripheral immunity in HD.
Area of Science:
- Neuroimmunology
- Genetics of neurodegenerative diseases
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT).
- Mutant huntingtin protein (mHTT) affects molecular pathways and immune cell regulation, but peripheral immune changes in HD are poorly understood.
Purpose of the Study:
- To investigate inflammatory and regulatory cytokine levels in peripheral organs of the BACHD mouse model of HD.
- To explore the immune alterations in organs beyond the central nervous system in HD.
Main Methods:
- Analysis of cytokine levels (IL-6, IL-12p70, TNF-α, IL-4, IL-5) in the kidney, heart, liver, and spleen of 12-month-old BACHD mice and wild-type (WT) controls.
- Utilized the BACHD mouse model, which closely mimics human HD.
Main Results:
- Significant alterations in cytokine profiles were observed across all analyzed peripheral organs in BACHD mice compared to WT.
- Specific increases in IL-6 (kidney), IL-6 and IL-12p70 (heart), IL-12p70 and TNF-α (liver), and IL-4 (spleen) were noted.
- A decrease in IL-5 and IL-6 levels was found in the spleen of BACHD mice.
Conclusions:
- The BACHD mouse model exhibits peripheral immune changes, indicating that immune dysregulation extends beyond the central nervous system in HD.
- These findings highlight the potential role of peripheral inflammatory responses in Huntington's disease pathogenesis.
- Further research is warranted to elucidate the mechanisms of immune signaling in peripheral organs in HD.
Abstract:
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the gene encoding the huntingtin protein (HTT). This expansion leads to the formation of mutant huntingtin protein (mHTT) that is expressed in many body tissue cells. The mHTT interacts with several molecular pathways within different cell types, affecting the regulation of the immune system cells. It is still very limited the understanding of the immune changes in peripheral tissues in HD. Herein, we investigated the levels of inflammatory and regulatory cytokines in peripheral organs (i.e. kidney, heart, liver and spleen) of the 12-month-old BACHD model of HD. This robust murine model closely resembles the human disease. We found significant changes in cytokine levels in all organs analyzed. Increased levels of IL-6 were found in the kidney, while levels of IL-6 and IL-12p70 were increased in the heart of BACHD mice in comparison with wild-type (WT) animals. In the liver, we observed enhanced IL-12p70 and TNF-α levels. In the spleen, there was an increase in the levels of IL-4 and a decrease in the levels of IL-5 and IL-6 in BACHD compared to WT. Our findings provide the first evidence that the BACHD model also exhibits immune changes in peripheral organs, opening an avenue for the investigation of the potential role played by peripheral inflammatory response in HD. Further studies are needed to systematically address the mechanisms and pathways underlying immune signaling in peripheral organs in HD.