1. Sign our petition calling on Cochrane to withdraw their review of Exercise Therapy for 'CFS'.
    Dismiss Notice
  2. Guest, the 'News in Brief' for the week beginning 15th July 2024 is here.
    Dismiss Notice
  3. Welcome! Read the Core Purpose and Values of our forum.
    Dismiss Notice

Cholinergic regulation of vascular endothelial function by human ChAT+ T cells 2023 Tarnawski et al

Discussion in 'Other health news and research' started by Andy, Apr 2, 2023.

Tags:
  1. Andy

    Andy Committee Member

    Messages:
    22,407
    Location:
    Hampshire, UK
    Significance
    ACh-releasing choline acetyltransferase (ChAT)+ T cells promote vasodilation and regulate blood pressure in mice, but human ChAT+ T cells and the molecular mechanisms by which ChAT-expression is regulated remain undefined. In this study, we identify primary ChAT+ T cells in patients and regulatory mechanisms for ChAT expression in T cells. Interestingly, cholinergic signals from T cells regulated vascular endothelial function in vitro.

    Abstract
    Endothelial dysfunction and impaired vasodilation are linked with adverse cardiovascular events. T lymphocytes expressing choline acetyltransferase (ChAT), the enzyme catalyzing biosynthesis of the vasorelaxant acetylcholine (ACh), regulate vasodilation and are integral to the cholinergic antiinflammatory pathway in an inflammatory reflex in mice. Here, we found that human T cell ChAT mRNA expression was induced by T cell activation involving the PI3K signaling cascade. Mechanistically, we identified that ChAT mRNA expression was induced following the attenuation of RE-1 Silencing Transcription factor REST-mediated methylation of the ChAT promoter, and that ChAT mRNA expression levels were up-regulated by GATA3 in human T cells. In functional experiments, T cell-derived ACh increased endothelial nitric oxide-synthase activity, promoted vasorelaxation, and reduced vascular endothelial activation and promoted barrier integrity by a cholinergic mechanism. Further, we observed that survival in a cohort of patients with severe circulatory failure correlated with their relative frequency of ChAT +CD4+ T cells in blood. These findings on ChAT+ human T cells provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.

    Open access, https://www.pnas.org/doi/10.1073/pnas.2212476120
     
    Andy, Apr 2, 2023
    #1
    hibiscuswahine, Michelle, alktipping and 5 others like this.
  2. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    14,088
    Location:
    London, UK
    AN interesting signalling system that might be relevant to ME.
     
    Jonathan Edwards, Apr 2, 2023
    #2
    FMMM1, Michelle, alktipping and 5 others like this.
  3. Hutan

    Hutan Moderator Staff Member

    Messages:
    28,009
    Location:
    Aotearoa New Zealand
    Mostly Swedish research.

    This is my understanding of the paper:

    Acetylcholine causes endothelial cells with muscarinic ACh-receptors that line blood vessels to produce nitric oxide, which relaxes the vascular smooth muscle and so causes vasodilation, and lowers blood pressure. Previously, it wasn't known where the acetylcholine (ACh) was coming from.

    The researchers, working from information gained with mouse models, found that a human T-cells subset produces a substance (ChaT) that produces acetylcholine, but only when the T-cells are activated. Unactivated T-cells, that is T-cells not reacting to antigens, don't produce the substance. The cells were activated by using anti-CD3/CD28 antibodies.

    The researchers were able to describe how T-cell activation resulted in the ChAT mRNA expression - it involves PI3K signalling. GATA3 upregulated ChAT mRNA. Exposure of the T-cells to norepinephrine (noradrenaline) didn't change ChAT expression.

    mRNA activation was found to take time, developing over 5 days. They found a huge variation in the quantity of the ChAT mRNA after T-cell activation in healthy donors.

    The researchers found that T cell-derived acetylcholine promoted vasodilation ex vivo, improved endothelial barrier integrity, and reduced inflammation-associated endothelial activation. They also found that the survival of patients with severe circulatory failure correlated with the numbers of ChAT+CD4+ T cells in their blood - higher numbers of these particular T-cells increased survival.
     
    Last edited: Apr 2, 2023
    Hutan, Apr 2, 2023
    #3
    Mij, SNT Gatchaman, Michelle and 5 others like this.
  4. Hutan

    Hutan Moderator Staff Member

    Messages:
    28,009
    Location:
    Aotearoa New Zealand
    If I'm understanding right, the researchers seem to be suggesting that acetylcholine produced by the activated T-cells acts locally, with most of the acetylcholine being inactivated before it gets very far. And so, it's very hard to detect the acetylcholine in vivo.

    Time for my breakfast. It will be interesting to think about how this might be relevant to ME/CFS.
     
    Hutan, Apr 2, 2023
    #4
    Mij, SNT Gatchaman, Michelle and 3 others like this.

Share This Page