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    Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis

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    Authors
    Szabady, Rose L.
    Louissaint, Christopher
    Lubben, Anneke
    Xie, Bailu
    Reeksting, Shaun
    Tuohy, Christine
    Demma, Zachary
    Foley, Sage
    Faherty, Christina S.
    Llanos-Chea, Alejandro
    Olive, Andrew J.
    Mrsny, Randall J.
    McCormick, Beth A.
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    UMass Chan Affiliations
    Graduate School of Biomedical Sciences
    Department of Microbiology and Physiological Systems
    Document Type
    Journal Article
    Publication Date
    2018-08-31
    Keywords
    Gastroenterology
    Neutrophils
    Amino Acids, Peptides, and Proteins
    Cells
    Cellular and Molecular Physiology
    Digestive System Diseases
    Gastroenterology
    Hemic and Immune Systems
    Lipids
    Pathological Conditions, Signs and Symptoms
    
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    Abstract
    Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.
    Source

    J Clin Invest. 2018 Aug 31;128(9):4044-4056. doi: 10.1172/JCI96817. Epub 2018 Aug 13. Link to article on publisher's site

    DOI
    10.1172/JCI96817
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/40771
    PubMed ID
    30102254
    Related Resources

    Link to Article in PubMed

    Rights
    Copyright © 2018, American Society for Clinical Investigation. Publisher pdf posted as allowed by the publisher's open access policy at https://www.jci.org/kiosks/terms.
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI96817
    Scopus Count
    Collections
    Morningside Graduate School of Biomedical Sciences Scholarly Publications
    UMass Chan Faculty and Researcher Publications

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