Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis
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.
UMass Chan Affiliations
Graduate School of Biomedical SciencesDepartment of Microbiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2018-08-31Keywords
GastroenterologyNeutrophils
Amino Acids, Peptides, and Proteins
Cells
Cellular and Molecular Physiology
Digestive System Diseases
Gastroenterology
Hemic and Immune Systems
Lipids
Pathological Conditions, Signs and Symptoms
Metadata
Show full item recordAbstract
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/JCI96817Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40771PubMed ID
30102254Related Resources
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