1. Academic Validation
  2. Cysteinyl leukotrienes and acetylcholine are biliary tuft cell cotransmitters

Cysteinyl leukotrienes and acetylcholine are biliary tuft cell cotransmitters

  • Sci Immunol. 2022 Mar 4;7(69):eabf6734. doi: 10.1126/sciimmunol.abf6734.
Maryam Keshavarz 1 2 Schayan Faraj Tabrizi 1 2 Anna-Lena Ruppert 3 Uwe Pfeil 1 2 Yannick Schreiber 4 Jochen Klein 5 Isabell Brandenburger 2 6 Günter Lochnit 7 Sudhanshu Bhushan 8 Alexander Perniss 1 2 Klaus Deckmann 1 2 Petra Hartmann 1 2 Mirjam Meiners 1 2 Petra Mermer 1 2 Amir Rafiq 1 2 Sarah Winterberg 3 Tamara Papadakis 1 2 Dominique Thomas 9 10 Carlo Angioni 9 Johannes Oberwinkler 11 Vladimir Chubanov 12 Thomas Gudermann 12 Ulrich Gärtner 1 Stefan Offermanns 2 6 Burkhard Schütz 3 Wolfgang Kummer 1 2
Affiliations

Affiliations

  • 1 Institute of Anatomy and Cell Biology, German Center for Lung Research, Justus Liebig University Giessen, Giessen, Germany.
  • 2 Excellence Cluster Cardio-Pulmonary Institute, Justus Liebig University Giessen, Giessen, Germany.
  • 3 Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany.
  • 4 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany.
  • 5 Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Goethe University Frankfurt, Frankfurt, Germany.
  • 6 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 7 Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany.
  • 8 Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus Liebig University Giessen, Giessen, Germany.
  • 9 Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany.
  • 10 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany.
  • 11 Philipps-Universität Marburg, Institut für Physiologie und Pathophysiologie, Marburg, Germany.
  • 12 Walther Straub Institute of Pharmacology and Toxicology, German Center for Lung Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Abstract

The gallbladder stores bile between meals and empties into the duodenum upon demand and is thereby exposed to the intestinal microbiome. This exposure raises the need for antimicrobial factors, among them, mucins produced by cholangiocytes, the dominant epithelial cell type in the gallbladder. The role of the much less frequent biliary tuft cells is still unknown. We here show that propionate, a major metabolite of intestinal bacteria, activates tuft cells via the short-chain Free Fatty Acid Receptor 2 and downstream signaling involving the cation channel transient receptor potential cation channel subfamily M member 5. This results in corelease of acetylcholine and cysteinyl leukotrienes from tuft cells and evokes synergistic paracrine effects upon the epithelium and the gallbladder smooth muscle, respectively. Acetylcholine triggers Mucin release from cholangiocytes, an epithelial defense mechanism, through the Muscarinic Acetylcholine Receptor M3. Cysteinyl leukotrienes cause gallbladder contraction through their cognate receptor CysLTR1, prompting emptying and closing. Our results establish gallbladder tuft cells as sensors of the microbial metabolite propionate, initiating dichotomous innate defense mechanisms through simultaneous release of acetylcholine and cysteinyl leukotrienes.

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