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

Rose Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, C Touhy, Zachary Demma, Sage E. Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall Mrsny, Beth McCormick

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10 Citations (Scopus)

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
Original languageEnglish
Pages (from-to)4044-4056
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number9
Early online date13 Aug 2018
DOIs
Publication statusPublished - 31 Aug 2018

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    Szabady, R., Louissaint, C., Lubben, A., Xie, B., Reeksting, S., Touhy, C., Demma, Z., Foley, S. E., Faherty, C. S., Llanos-Chea, A., Olive, A. J., Mrsny, R., & McCormick, B. (2018). Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis. Journal of Clinical Investigation, 128(9), 4044-4056. https://doi.org/10.1172/JCI96817