• Bba Mol Basis Dis · Jan 2018

    The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.

    • Fabienne Gally, Deviyani M Rao, Carsten Schmitz, Kelley L Colvin, Michael E Yeager, and Anne-Laure Perraud.
    • Linda Crnic Institute for Down Syndrome Research, CO, United States; National Jewish Health, Dept. of Biomedical Research, CO, United States.
    • Bba Mol Basis Dis. 2018 Jan 1; 1864 (1): 126-132.

    AbstractTrisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS. Furthermore, elevated Reactive Oxygen Species (ROS) are well documented in individuals with DS, further exacerbating inflammatory processes. Chronic inflammation and oxidative stress are often precursors of subsequent tissue destruction and pathologies, which affect a majority of persons with DS. Together with ROS, the second messenger ion Ca2+ plays a central role in immune regulation. TRPM2 (Transient Receptor Potential Melastatin 2) is a Ca2+-permeable ion channel that is activated under conditions of oxidative stress. The Trpm2 gene is located on human Chromosome 21 (Hsa21). TRPM2 is strongly represented in innate immune cells, and numerous studies have documented its role in modulating inflammation. We have previously found that as a result of suboptimal cytokine production, TRPM2-/- mice are highly susceptible to the bacterial pathogen Listeria monocytogenes (Lm). We therefore used Lm infection to trigger and characterize immune responsiveness in the DS mouse model Dp10(yey), and to investigate the potential contribution of TRPM2. In comparison to wildtype (WT), Dp10(yey) mice show an increased resistance against Lm infection and higher IFNγ serum concentrations. Using a gene elimination approach, we show that these effects correlate with Trpm2 gene copy number, supporting the notion that Trpm2 might promote hyperinflammation in DS.Copyright © 2017. Published by Elsevier B.V.

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