Cannabinoids in asthma, allergic diseases and viral infections
The human endogenous cannabinoid system (ECS) is involved in many physiological processes. It consists of the cannabinoid receptors (CBRs), the endogenous ligands (anandamide and 2-arachidonoylglycerol) and the proteins related to their synthesis and degradation.132 Cannabinoid receptor 1 (CB1) and 2 (CB2) are the main CBRs. CB1 is largely expressed in the central nervous system but also in peripheral tissues and immune cells. CB2 is mainly expressed in immune cells but also in other cell types such as progenitor neurons. The biosynthesis and inactivation of endocannabinoids involve five main enzymes: N‑acyl-phosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD),sn ‑1‑specific diacylglycerol lipase-α (DGLα), DGLβ, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). The main product of endocannabinoids inactivation is the AA (Fig. 1) .133,134 The role of cannabinoids in allergic diseases is still a bit controversial.135 Sukawaraet al demonstrated that endocannabinoids limited mast cell maturation and activation in human airway mucosa and skin through CB1.136,137 Tetrahydrocannabinol (THC) and cannabidiol (CBD) attenuated airway allergic inflammation, decreased cytokine production, cell infiltration, mucus secretion and bronchial hyperresponsiveness in mice.138-140 Similarly, the synthetic agonist CP55,940 induced lung protection in ovalbumine (OVA)-induced asthma guinea pig models via CB1 and CB2.141 In keratinocytes, CB1 prevented transepithelial water loss and skin inflammation, cell infiltration and cytokine production in atopic dermatitis mouse model.142 Anandamide and different CB1 agonists also accelerated skin barrier recovery and reduced pro-inflammatory cytokine production and cell recruitment.143,144 Several cannabinoids have also shown a protective role in allergic contact dermatitis by reducing inflammatory responses.145-147CB1 activation may also induce bronchodilation in the airways.141,148 In human bronchial epithelial cells, the synthetic agonist WIN55212-2 restored the epithelial barrier disruption induced by RV.149 In addition, WIN55212-2 decreased the immediate anaphylactic reaction in a mouse model of peanut allergy, and promoted the generation of allergen-specific regulatory T cells.150 Currently, different studies suggest the therapeutic potential of cannabinoids in COVID-19 pandemic.151-153 In contrast, Frei et al showed that CB2 activation enhanced migratory responsiveness of eosinophils in an OVA-asthma mouse models.154 Accordingly, the lack of CB2 decreased allergic inflammation in asthma and dermatitis mouse model.155 This result correlated with increased number of NK cells and reduced number of ILC2s in the lung of CB2 knockout mice, demonstrating that NK cells are negative regulators of ILC2s.156 Interestingly, it has been described that mRNA expression levels of CB1 are upregulated in tonsils and peripheral blood of patients with allergic rhinitis, atopic dermatitis, and food allergy, but the functional relevance remains unknown.157 These studies suggest that the ECS could be explored as a potential therapeutic target in the treatment of asthma, allergic and skin diseases and viral infections.