Effect of endocannabinoid system and cannabimimetic compounds in the control of mast cells: possible implication in acute and chronic inflammation

Mast cells are immune competent cells strategically localised at the sites directly interfacing with the external environment, which, in case of injury, regulate the immune response by the release of a plethora of both pre-formed and newly-synthesised mediators. However, although the main goal of mast cell activation is to initiate the inflammatory reaction, and thus maintain internal homeostasis, the consequences of dysregulated mast cell activation could be to chronically activate the inflammatory response as occurs in arthritis, inflammatory bowel diseases, atherosclerosis and asthma. Therefore, much effort has been made to develop compounds that act to prevent mast cell degranulation. Several evidences suggested that cannabinoids and palmitoylethanolamide are nowadays considered as an emerging class of regulators of mast cell behaviour. We, firstly, focus on the action of cannabimimetic compounds in the control of mast cell in vitro, in mast cell isolated from human biopsies of endometritis women and peritoneum of rats. To study mast cell functionality in vitro is sometime inappropriate since the considerable degree of mast cell heterogeneity both in respect to their morphology, expression of proteins, and, above all, to theirs different sensitivity to stimulants, therefore the study continued in an animal model of mast cell dependent chronic inflammation, as granuloma. The activation of endocannabinoid system or the up-regulation of palmitoylethanolamide tone, by the control of mast cell activation and the subsequent release of pro-inflammatory and pro-angiogenic mediators, significantly reduced granuloma formation in rat. Moreover our data evidenced that the PEA modulation of mast cells resulted useful also in the management of granuloma-associated pain. In fact PEA through the control of mast cell-nerves crosstalk reduced the mechanical allodynia in granuloamtous rats, in well accordance with the recently demonstrated involvement of a neuro-immune axis deregulation, in the ethilogy of inflammatory disease. The cannabimimetic control of neuro-immune axis was finally studied in a model of acute intestinal inflammation in mice. The administration of cannabidiol, by the blockage of fatty Acid Amide hydrolase, in septic mice prevented the activation of enteric glial cells in parallel with the activation of immune cells (mast cell and macrophages). The control of neuro-immune axis operated by cannabidiol finally accounted for an anti-inflammatory and a protective effect in septic mice. According to the here reported evidences for a cannabinomimetic control of mast cell, it is reasonable to propose that these compounds, including palmitoylethanolamide and its congeners, could represent a possible candidate for treating several acute and chronic inflammatory diseases, recognizing a common mast cell activation, such as dermatitis, inflammatory gastrointestinal syndrome and granuloma formation