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Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis
Rose L. Szabady, … , Randall J. Mrsny, Beth A. McCormick
Rose L. Szabady, … , Randall J. Mrsny, Beth A. McCormick
Published August 13, 2018
Citation Information: J Clin Invest. 2018;128(9):4044-4056. https://doi.org/10.1172/JCI96817.
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Research Article Gastroenterology

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

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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.

Authors

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

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Figure 4

AMEND is present in mouse intestine.

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AMEND is present in mouse intestine.
(A) Colonic scrapings from 5 WT or ...
(A) Colonic scrapings from 5 WT or Mdr1a–/– FVB mice were pooled, enriched for lipids, and tested in the 96-well migration assay as in Figure 2. Data are shown as mean ± SEM from 3 independent experiments. **P < 0.01, 1-way ANOVA. (B) Indicated sample was pretreated with FAAH for 30 minutes at 37°C. *P = 0.01. (C) Intestinal mucosal scrapings from WT and Mdr1a–/– FVB mice were lipid extracted (modified Folch method) and analyzed by MS. Mice were pooled in groups of 3. Data shown are from 3 pooled groups. Semiquantitative analysis was performed as in Figure 2.

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