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

Research output: Contribution to journalArticle

7 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
DOIs
Publication statusPublished - 31 Aug 2018

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Endocannabinoids
P-Glycoprotein
Neutrophils
Homeostasis
Inflammation
Epithelial Cells
Cannabinoid Receptor CB2
Intestinal Secretions
Lipids
Ethanolamine
Eicosanoids
Neutrophil Infiltration
Chemotactic Factors
Multiple Drug Resistance
Inflammatory Bowel Diseases
Intestines
Signal Transduction
Anti-Inflammatory Agents
Pathology

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Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis. / Szabady, Rose; Louissaint, Christopher; Lubben, Anneke; Xie, Bailu; Reeksting, Shaun; Touhy, C; Demma, Zachary; Foley, Sage E.; Faherty, Christina S.; Llanos-Chea, Alejandro; Olive, Andrew J.; Mrsny, Randall; McCormick, Beth .

In: Journal of Clinical Investigation, Vol. 128, No. 9, 31.08.2018, p. 4044-4056.

Research output: Contribution to journalArticle

Szabady, R, Louissaint, C, Lubben, A, Xie, B, Reeksting, S, Touhy, C, Demma, Z, Foley, SE, Faherty, CS, Llanos-Chea, A, Olive, AJ, Mrsny, R & McCormick, B 2018, 'Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis', Journal of Clinical Investigation, vol. 128, no. 9, pp. 4044-4056. https://doi.org/10.1172/JCI96817
Szabady, Rose ; Louissaint, Christopher ; Lubben, Anneke ; Xie, Bailu ; Reeksting, Shaun ; Touhy, C ; Demma, Zachary ; Foley, Sage E. ; Faherty, Christina S. ; Llanos-Chea, Alejandro ; Olive, Andrew J. ; Mrsny, Randall ; McCormick, Beth . / Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 9. pp. 4044-4056.
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AB - 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

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