The endocannabinoid system drives eosinophil infiltration during eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic, inflammatory, and antigen-driven disease of the esophagus. Total transcriptome data revealed alterations in the endocannabinoid system (ECS), in particular, downregulation of monoacylglycerol lipase (MGL) in biopsies of patients with active EoE. We investigated the consequence of MGL downregulation in mucosal biopsies of patients, and its implications for EoE development, such as recruitment of eosinophils. Levels of MGL substrate 2-arachidonoylglycerol (2-AG), MGL enzyme activity and MGL co-localization with epithelial cells were determined in mucosal esophageal biopsies of EoE patients. Supernatant of human primary esophageal epithelial cells was used to determine eosinophil migration and activation. An inducible mouse model of EoE was used to test MGL inhibition and cannabinoid (CB) receptor antagonism in vivo. MGL expression in esophageal epithelial cells from active EoE patients is decreased, while 2-AG is increased compared to controls. Inhibition of MGL in epithelial cells leads to a pro-inflammatory phenotype capable of attracting eosinophils via CB2. Similarly, the EoE mouse model indicates that absence of MGL results in higher eosinophil infiltration. Targeting CB2 reduced the number of infiltrating eosinophils in the esophagi of mice. This study is the first of its kind to investigate the involvement of altered expression of ECS components in EoE, and partly explains recent findings of more inflammatory features post EoE-treatment in cannabis users. Our findings could pave the way for research into alternative treatment options for EoE and call for caution regarding the use of cannabinoids in EoE.