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  • In summary our findings support the hypothesis that activati

    2022-01-19

    In summary, our findings support the hypothesis that activation of GPR55 protects against deficits in neurogenesis induced by inflammatory insult both in vitro and in vivo through direct targeting of NSCs. Better understanding of the mechanisms by which GPR55 provides neuroprotection is critically necessary and may provide a more directed target for future therapeutics.
    Author contributions J.D.H. designed and performed experiments, wrote the manuscript, and supervised the project. V.Z.R. designed animal experiments. S.G. and M.W. performed in vitro experiments and histology. S.R. aided in microglial analysis. S.R and U.S aided in transcriptome analysis. Y.P. supervised the project and refined the manuscript.
    Introduction Endocannabinoids are polyunsaturated fatty acids synthesized on demand upon distinct physiological stimuli. Arachidonoyl ethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG) are the best-characterized members of this group [1,2]. Endocannabinoids bind with different affinities to classical CB1 and CB2 receptors coupled to Gi/o proteins causing adenylyl cyclase activity inhibition, increased potassium channels conductance and decreased conductance of calcium channels. In addition, CB1 and CB2 receptors regulate phosphorylation and activation of mitogen activated protein kinases (MAPKs) [3]. Endocannabinoids modulate distinct innate and adaptive immune functions [4], including prostaglandin production during inflammation [5], T and B cell proliferation [[6], [7], [8]], neutrophil degranulation and chemotaxis [9], and cytokine production in activated leukocytes [10]. Although many endocannabinoid effects in immune hydroxychloroquine sulfate are mediated by CB1 and CB2 receptors [11,12], some others are not [13]. In particular, AEA blocks T-type and L-type Ca2+ channels [14,15], acts as a partial TRPV1 agonist [16], and activates PPAR [17] and GPR55 receptors [18]. Mast cells (MCs) have an important role in the physiopathology of inflammation [19,20]. They are well known initiators of allergic reactions due to the presence of the high affinity IgE receptor (FcεRI) on their cellular membrane, and secrete a number of pro-inflammatory and immunoregulatory mediators after activation [21,22]. Intensive research, directed to identify compounds able to inhibit IgE/Ag-induced MCs activation, has been conducted worldwide to better cope with the important burden of allergic diseases [[23], [24], [25]]. IgE/Ag-mediated cross-linking of FcεRI activates a complex signaling cascade that involves the Src family kinases Lyn and Fyn [26,27]. In turn, phosphorylation of specific substrates and the formation of multiple protein aggregates lead to the release of preformed mediators stored in granules in a PKC- and calcium-dependent process known as anaphylactic degranulation [28,29]. In addition to granule content exocytosis, the rise in intracellular Ca2+ concentration [Ca2+] contributes to the activation of specific transcription factors (such as NFAT, AP-1 and NFκB), inducing cytokine mRNA synthesis and cytokine secretion [[30], [31], [32]]. Like other cells in the immune system, MCs respond to endocannabinoids and express cannabinoid receptors [33]. It is assumed that the anti-inflammatory effects of cannabinoids used for the treatment of MCs-associated diseases, such as pain and inflammation [34], arthritis [35], colitis [36], ocular disease [37] and atopic dermatitis [38], are related to MC activity inhibition. Although it is known that endocannabinoids regulate MC maturation [39] and inhibit mediator secretion [40,41], a detailed description of the effects of cannabinoids on MCs, and the identification of the molecular targets of those compounds is far from complete. The objectives of this work were to study the effects of AEA on IgE/Ag-induced degranulation of bone marrow-derived mast cells (BMMCs) and to determine the role of cannabinoid receptors and Ca2+ mobilization on these effects. This research shows that AEA inhibits BMMCs degranulation by mechanisms involving both CB2 and GPR55 receptor activation.