Publications

    • 16 SEP 16
    • 0
    A new edge to immune surveillance by the neural system

    A new edge to immune surveillance by the neural system

    A recent paper published in Nature demonstrates a multifaceted relation between enteric glial cells (EGC), intestinal epithelia, and ILC3, via the EGC release of neurotrophic factors, a structurally related group of ligands within the TGF-β superfamily of signaling molecules and IL-22 produced by ILC3.

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    • 14 SEP 16
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    Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

    Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

    P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.

    • 09 SEP 16
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    Intestinal dysfunction in Parkinson’s disease: Lessons learned from translational studies and experimental models

    Intestinal dysfunction in Parkinson’s disease: Lessons learned from translational studies and experimental models

    Symptoms of digestive dysfunction in patients with Parkinson’s disease (PD) occur at all stages of the disease, often preceding the onset of central motor symptoms. On the basis of these PD-preceding symptoms it has been proposed that PD could initiate in the gut, and that the presence of alpha-synuclein aggregates, or Lewy bodies in the enteric nervous system might represent one of the earliest signs of the disease. Following this hypothesis, much research has been focused on the digestive tract to unravel the mechanisms underlying the onset and progression of PD, with particular attention to the role of alterations in enteric neurotransmission in the pathophysiology of intestinal motility disturbances. There is also evidence suggesting that the development of central nigrostriatal neurodegeneration is associated with the occurrence of gut inflammation, characterized by increments of tissue pro-inflammatory markers and oxidative stress, which might support conditions of bowel neuromotor abnormalities. The present review intends to provide an integrated and critical appraisal of the available knowledge on the alterations of enteric neuromuscular pathways regulating gut motor activity both in humans and preclinical models of PD. Moreover, we will discuss the possible involvement of neuro-immune mechanisms in the pathophysiology of aberrant gastrointestinal gut transit and neuromuscular activity in the small and large bowel.

    • 11 AUG 16
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    Acetylcholine producing T-cells in the intestine affect antimicrobial peptide expression and microbial diversity

    Acetylcholine producing T-cells in the intestine affect antimicrobial peptide expression and microbial diversity

    The cholinergic anti-inflammatory pathway reduces systemic TNF via acetylcholine producing memory T-cells in the spleen. These choline acetyltransferase (ChAT) expressing T-cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT-eGFP reporter mice. CD4Cre mice were crossed to ChATfl/fl mice to achieve specific deletion of ChAT in CD4+ T-cells. We observed that the majority of ChAT expressing T-cells in the human and mouse intestine have characteristics of Th17 cells, and co-express IL17A, IL22 and RORC. The generation of ChAT expressing T-cells was skewed by dendritic cells after activation of their adrenergic receptor β2. To evaluate ChAT T-cell function, we generated CD4 specific ChAT deficient mice. CD4ChAT-/- mice showed a reduced level of epithelial antimicrobial peptides (AMP) lysozyme, defA, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT-/- mice. We conclude that ChAT expressing T-cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT expressing T-cells may function to mediate the host AMP secretion, microbial growth and expansion.