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

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.

Shigella flexneri adherence factor expression in in vivo-like conditions

“…To support the biofilm data and our previous induced HT-29 adherence observations (30, 31), we performed adherence analysis on a human intestinal organoid-derived epithelial monolayer (HIODEM) model. The model is derived from stem cells isolated from intestinal tissue, propagated as organoids, and subsequently trypsinized and seeded onto transwells to generate a two-dimensional (2-D) polarized, differentiated model of the intestinal epithelium in which enterocytes, mucus-producing goblet cells, and antigen sampling M cells are present (34–38). With the model derived from the ascending colon, S. flexneri 2457T subcultured in IVLCs displayed putative adherence factors contacting the epithelial cells (Figure 2).…”

A new target to ameliorate the damage of periodontal disease: The role of transient receptor potential vanilloid type‐1 in contrast to that of specific cannabinoid receptors in rats

“…In recent years, many studies have focused on the research of the ECS and its implication on immune and inflammatory diseases, including periodontal disease . ‒ Most of these studies have approached this issue through cells cultures such as human gingival fibroblasts and ligament periodontal cells .…”

“…In recent years, many studies have focused on the research of the ECS and its implication on immune and inflammatory diseases, including periodontal disease. [31][32][33] Most of these studies have approached this issue through cells cultures such as human gingival fibroblasts and ligament periodontal cells. 34 However, our research group reported anti-inflammatory effects on gingival tissue and osteoprotective effects on alveolar bone induced by both a CB2r and a CB1r agonist (HU308 and meth-AEA, respectively), in a model of LPS-induced periodontal disease in vivo.…”

Cannabis, the Endocannabinoid System and Immunity—the Journey from the Bedside to the Bench and Back

“…They demonstrated that the transporter P-glycoprotein (P-gp) secretes endocannabinoids into the intestinal lumen that counteract the pro-inflammatory actions of the neutrophil chemoattractant eicosanoid hepoxilin A3. Moreover, the anti-inflammatory actions of P-gp—secreted endocannabinoids—are mediated by CB2 receptors on neutrophils [ 34 ]. Kapellos et al recently published that the CB2 deficiency exacerbates acute neutrophils mobilization to sites of inflammation [ 35 ].…”