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      Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells

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          Abstract

          Human Gingival Mesenchymal Stem Cells (hGMSCs) are multipotential cells that can expand and differentiate in culture under specific and standardized conditions. In the present study, we have investigated whether in vitro pre-treatment of hGMSCs with Cannabidiol (CBD) can influence their expression profile, improving the therapeutic potential of this cell culture. Following CBD treatment (5 μM) for 24 h, gene expression analysis through Next Generation Sequencing (NGS) has revealed several genes differentially expressed between CBD-treated hGMSCs (CBD-hGMSCs) and control cells (CTR-hGMSCs) that were linked to inflammation and apoptosis. In particular, we have demonstrated that CBD treatment in hGMSCs prevented the activation of the NALP3-inflammasome pathway by suppressing the levels of NALP3, CASP1, and IL18, and in parallel, inhibited apoptosis, as demonstrated by the suppression of Bax. CBD treatment was also able to modulate the expression of the well-known mesenchymal stem cell markers (CD13, CD29, CD73, CD44, CD90, and CD166), and other surface antigens. Specifically, CBD led to the downregulation of genes codifying for antigens involved in the activation of the immune system (CD109, CD151, CD40, CD46, CD59, CD68, CD81, CD82, CD99), while it led to the upregulation of those implicated in the inhibition of the immune responses (CD47, CD55, CD276). In conclusion, the present study will provide a new simple and reproducible method for preconditioning hGMSCs with CBD, before transplantation, as an interesting strategy for improving the hGMSCs molecular phenotype, reducing the risk of immune or inflammatory reactions in the host, and in parallel, for increasing their survival and thus, their long-term therapeutic efficacy.

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          Most cited references44

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          Interleukin-18 regulates both Th1 and Th2 responses.

          Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-gamma. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglia. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.
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            IL-1β Processing in Host Defense: Beyond the Inflammasomes

            Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms.
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              Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.

              Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                24 November 2016
                2016
                : 7
                : 559
                Affiliations
                [1] 1Experimental Neurology Laboratory, IRCCS Centro Neurolesi “Bonino-Pulejo” Messina, Italy
                [2] 2Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University “G. d'Annunzio” Chieti-Pescara, Chieti, Italy
                [3] 3Department of Medicine and Aging Sciences, University “G. d'Annunzio” Chieti-Pescara, Chieti, Italy
                [4] 4Council for Research and Experimentation in Agriculture - Research Centre for Industrial Crops (CRA-CIN) Rovigo, Italy
                [5] 5Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale Novara, Italy
                Author notes

                Edited by: Gaetano Santulli, Columbia University, USA

                Reviewed by: Stefania Ceruti, University of Milan, Italy; Yvonne Alexander, The University of Manchester, UK

                *Correspondence: Emanuela Mazzon emazzon.irccs@ 123456gmail.com

                This article was submitted to Clinical and Translational Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00559
                5121123
                27932991
                7e81004f-6084-40b1-b83c-116159fb2b3a
                Copyright © 2016 Libro, Scionti, Diomede, Marchisio, Grassi, Pollastro, Piattelli, Bramanti, Mazzon and Trubiani.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 September 2016
                : 04 November 2016
                Page count
                Figures: 6, Tables: 8, Equations: 0, References: 64, Pages: 17, Words: 10868
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                cannabidiol,human gingival mesenchymal stem cells,immunophenotype,next generation sequencing,inflammasome

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