Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ

Background: Because many chronic inflammatory and allergic disorders are intimately linked to excessive mast cell (MC) numbers and activation, it is clinically important to understand the physiologic mechanisms preventing excess MC accumulation/degranulation in normal human tissues. Objective: Because endocannabinoids are increasingly recognized as neuroendocrine regulators of MC biology, we investigated how cannabinoid receptor (CB) 1 signaling affects human mucosal-type mast cells (hMMCs). Methods: Using organ-cultured nasal polyps as a surrogate tissue for human bronchial mucosa, we investigated how CB1 stimulation, inhibition, or knockdown affects hMMC biology using quantitative (immuno) histomorphometry and electron microscopy. Results: Kit 1 hMMCs express functional CB1 in situ. Blockade of CB1 signaling (with the specific CB1 antagonist N-(piperidin1- yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1Hpyrazole- 3-carboxamide [AM251] or CB1 gene knockdown) enhanced hMMC degranulation and increased total numbers without affecting their proliferation in situ. This suggests that inhibiting CB1 signaling induces hMMC maturation from resident progenitor cells within human mucosal stroma. hMMC maturation was induced at least in part through upregulating stem cell factor production. Both the prototypic endocannabinoid anandamide and the CB1-selective agonist arachidonyl-2-chloroethylamide effectively counteracted secretagogue-triggered excessive hMMC degranulation. Conclusions: The current serum-free nasal polyp organ culture model allows physiologically and clinically relevant insights into the biology and pharmacologic responses of primary hMMCs in situ. In human airway mucosa hMMC activation and maturation are subject to a potent inhibitory endocannabinoid tone through CB1 stimulation. This invites one to target the endocannabinoid system in human airway mucosa as a novel strategy in the future management of allergic diseases.