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Cannabinoids and Inflammations of the Gut-Lung-Skin Barrier

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Cannabinoids and Inflammations of the Gut-Lung-Skin Barrier Journal of Personalized Medicine Review Cannabinoids and Inflammations of the Gut-Lung-Skin Barrier Cristian Scheau 1 , Constantin Caruntu 1,2 , Ioana Anca Badarau 1, Andreea-Elena Scheau 3, Anca Oana Docea 4,* , Daniela Calina 5,* and Ana Caruntu 6,7 1 Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; [email protected] (C.S.); [email protected] (C.C.); [email protected] (I.A.B.) 2 Department of Dermatology, “Prof. N. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania 3 Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania; [email protected] 4 Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 5 Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 6 Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania; [email protected] 7 Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania * Correspondence: [email protected] (A.O.D.); [email protected] (D.C.) Abstract: Recent studies have identified great similarities and interferences between the epithelial layers of the digestive tract, the airways and the cutaneous layer. The relationship between these structures seems to implicate signaling pathways, cellular components and metabolic features, and has led to the definition of a gut-lung-skin barrier. Inflammation seems to involve common features in these tissues; therefore, analyzing the similarities and differences in the modulation of its biomarkers can yield significant data promoting a better understanding of the particularities of Citation: Scheau, C.; Caruntu, C.; specific signaling pathways and cellular effects. Cannabinoids are well known for a wide array of Badarau, I.A.; Scheau, A.-E.; Docea, beneficial effects, including anti-inflammatory properties. This paper aims to explore the effects of A.O.; Calina, D.; Caruntu, A. natural and synthetic cannabinoids, including the components of the endocannabinoid system, in Cannabinoids and Inflammations of relation to the inflammation of the gut-lung-skin barrier epithelia. Recent advancements in the use the Gut-Lung-Skin Barrier. J. Pers. of cannabinoids as anti-inflammatory substances in various disorders of the gut, lungs and skin Med. 2021, 11, 494. https://doi.org/ are detailed. Some studies have reported mixed or controversial results, and these have also been 10.3390/jpm11060494 addressed in our paper. Academic Editor: David S. Gibson Keywords: cannabinoids; inflammation; gut-lung-skin barrier; signaling pathways; inflamma- Received: 10 April 2021 tory biomarkers Accepted: 28 May 2021 Published: 31 May 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in The epithelial lining is the first line of defense against the abundance of aggressive published maps and institutional affil- factors in the environment. The integer epithelium represents a mechanical barrier, while iations. the physiological processes occurring in and between the cells contribute to dynamic and complex protection from physical, chemical and biological agents. The immune role of the epithelial layer is supported by various cells and cytokines, which show common features between the gastrointestinal tract and the pulmonary and cutaneous systems [1–3]. These Copyright: © 2021 by the authors. similarities in role and functioning have led recent research in the direction of exploring Licensee MDPI, Basel, Switzerland. the gut-lung-skin barrier as an entity that not only shows common elements but also This article is an open access article interactions [4]. The cross-talk between these three regions refers to various signaling distributed under the terms and molecules which are mainly involved in local and systemic inflammation [5]. conditions of the Creative Commons This paper focuses on the roles of cannabinoids in inflammation affecting the gut-lung- Attribution (CC BY) license (https:// skin barrier and brings forward the similarities and distinctions in the pathophysiology creativecommons.org/licenses/by/ of the inflammatory conditions affecting these systems. The latest advancements in the 4.0/). J. Pers. Med. 2021, 11, 494. https://doi.org/10.3390/jpm11060494 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, 494 2 of 26 field are discussed and supported by the available in vitro and in vivo evidence in the recent literature, as well as the human studies which have been undertaken to validate the effectiveness and safety of cannabinoids in the epithelial inflammation of the gut-lung- skin barrier. 2. The Gut-Lung-Skin Barrier The gut-lung-skin barrier is a virtual structure encompassing the epithelium of the di- gestive tract, the pulmonary system and the cutaneous layer. More and more often, studies cite similarities and interactions in the immune response regulated in these structures [4–6]. The recently described T helper 17 (Th17) subset of cells and their regulatory pathway provide further evidence validating the unity of the immune response and regulation in the gut-lung-skin barrier [7]. These cells are capable of producing various cytokines such as granulocyte colony-stimulating factor (G-CSF) and interleukins (ILs) -8 and -22, and trigger the synthesis of effectors producing IL-17 and interferon-gamma (IFN-γ)[8]. Furthermore, Th17 cells are involved in the interactions between the microbiota of the specific tissue and the host, regulating the immune response [8]. The most prominent cytokines involved in the protection against microbial infection are IL-17 and IL-22, which increase the release of antimicrobial peptides, neutrophil recruitment and granulopoiesis while maintaining the integrity of the epithelial layer in boundary tissues [9]. When IL-17 fails due to insufficient expression, a large variety of cutaneous, pulmonary and gastrointestinal infections may occur, accompanied by significant inflammation [10–12]. Some infectious agents such as Staphylococcus aureus are capable of stimulating its expression [13]. IL-22 also contributes to the immune response against various infectious diseases of the gut-lung-skin barrier and exhibits pro-inflammatory roles by enhancing the effects of tumor necrosis factor-alpha (TNF-α), and by activating various other cytokines [9,14]. However, the gut-lung-skin barrier cross-talk in inflammation is not limited to the activity of Th17 cells. The epithelial cells produce thymic stromal lymphopoietin (TSLP), a cytokine similar to IL-7, which is involved in the allergic response and is a key factor in the onset of allergic inflammation in the skin, lungs and gastrointestinal tract [15]. TSLP is considered to be a biomarker for disruptions of the epithelial integrity, and was cited as a determining and aggravating factor in a variety of allergy models, including ovalbumin (OVA)-induced asthma, atopic dermatitis and allergic diarrhea [16]. Sustained inflammatory processes in the gut-lung-skin barrier develop similar com- plications, regardless of the initial location of the inflammation. Among the common comorbidities are metabolic syndrome, cardiovascular events and bone loss [5,17,18]. These may be explained by the increased production of TNF-α, which is an essential mediator of chronic inflammation and is usually accompanied by IL-4, IL-6 and IL-17, increasing the risk of the aforementioned complications, as well as favoring the appearance of other metabolic conditions [5,19,20]. Because inflammation is the cornerstone of many pathological conditions, including cancer, the possible connections and interferences between inflammatory processes in different organs and systems have substantial implications. Inflammatory conditions, regardless of their substrate or location, benefit from relatively specific management, which includes one or several anti-inflammatory drugs. However, due to adverse effects and interactions, there is a growing interest in medicinal-grade natural compounds that have demonstrated their effectiveness and usually act through dedicated receptors that are widely distributed in the human body. These substances have been labeled ‘phytochemi- cals’, and some examples include capsaicin, curcumin, resveratrol and cannabinoids [21–24]. Curcumin, resveratrol, gingerol, and ginsenoside have demonstrated antioxidant and anti- inflammatory effects by modulating the MAP and NF-κB pathways, making them excellent candidates in the treatment of atopic dermatitis [25]. Multiple in vivo and in vitro studies have outlined the chemopreventive properties of whole-fruit substances in skin carcino- genesis, where carotenoids, polyphenols, flavonoids and anthocyanins have demonstrated pro-apoptotic, antiproliferative, and ROS-reducing effects in basal and squamous cell car- J. Pers. Med. 2021, 11, 494 3 of 26 cinoma models [26–29]. Capsaicin’s effects on chemonociception were fundamental in cutaneous pathophysiology research, but its applications have extended from skin pain modulation to various local and system-wide pathologies, including malignancies [30–32]. Cannabinoids, in particular, show great promise due to the mediation of their actions by the dedicated cannabinoid receptors, which serve the activity of the endocannabinoid system but also respond to the administration of natural or synthetic cannabinoids. 3. Cannabinoids
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