Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis
AuthorsSzabady, Rose L.
Faherty, Christina S.
Olive, Andrew J.
Mrsny, Randall J.
McCormick, Beth A.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins
Cellular and Molecular Physiology
Digestive System Diseases
Hemic and Immune Systems
Pathological Conditions, Signs and Symptoms
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AbstractNeutrophil 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40771
RightsCopyright © 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.