7.0 Cannabinoid signaling and skin inflammation
Inflammatory skin conditions such as acne, allergic contact dermatitis (ACD), dermatomyositis, psoriasis and scleroderma are associated with substantial systemic burden, and social and psychological effects. The negative psychological effects may impact greatly on the patient’s quality of life, especially when pain and pruritus are present (Scheau et al., 2020). Fibrotic changes that occur in the course of these diseases, may result in permanent scarring, thus increasing the disease burden (Sanclemente et al., 2014; Chovatiya and Silverberg, 2019). Among the recently investigated therapeutic options for the management of inflammatory skin conditions are cannabinoids. As an advantage, transcutaneous administration of cannabinoids avoids first-pass metabolism, and produces a steady and prolonged drug infusion, with minimal adverse effects (Huestis, 2007).
In ACD, primary exposure to allergen results in absorption of the allergen through the stratum corneum and covalent binding of the allergen to keratinocytes in the stratum spinosum, subsequently initiating innate immune responses (Kaplan et al., 2012). Subsequent exposure to the same allergen or similar molecules triggers a delayed-type hypersensitivity reaction mediated by effector T cells and various cytokines and chemokines (Novak-Bilić et al., 2018). This action can be inhibited by cannabinoids. In a study on polyinosinic:polycytidylic acid-induced ACD in human keratinocyte cells, administration of cannabidiol reduced inflammation by inhibiting monocyte chemotactic protein-2, IL-6, IL-8 and TNF-α (Petrosino et al., 2018). In vitro , cannabidiol decreases T and B-cell-mediated effects including T-helper 17 responses, in splenocytes and also inhibits, in addition to previously mentioned pro-inflammatory cytokines, IL-17 and interferon (Kozela et al., 2015; Harvey et al., 2014). CB1-mediated downregulation of mast cells, reduction in the production of chemokines such as CCL2, CCL8, and CXL10, and activation of PPARs are possible mechanisms underlying the inhibition of phorbol ester-induced acute inflammation by CB1 agonists (Kim et al., 2018). Non CB1/CB2-mediated anti-inflammatory effects of cannabinoids such as topical Δ9-THC in ACD have also been reported, especially in 2,4-dinitrofluorobenzene-induced ACD (Gaffal et al., 2013). Thus, cannabidiol can suppress inflammatory component of ACD with minimal or no cytotoxic effects.
Macrophages are important players in the inflammatory response to pathogens and tissue damage such as in necrotic tissues (Brancato et al., 2011). When exposed to inflammatory signals, macrophages polarisation is favoured toward the pro-inflammatory M1 phenotype, with subsequent release of numerous cytokines including IL-1, IL-6, IL-8, IL-12 and TNF-α (Duque and Descoteaux, 2014). Activation of CB2 has been shown to inhibit M1 polarisation and also enhance polarisation toward the anti-inflammatory M2 phenotype (Luo et al., 2018). This argument, however, opens the door to questions on the role of CB2 and M2 macrophages in fibrosis, since activation of CB2 inhibits fibrosis (Li et al., 2016; Wang et al., 2016; Tang et al., 2018) whereas M2 activation promotes fibrosis (He et al., 2013; Duru et al., 2016). Additional studies in this area is thus needed to fully elucidate the relation between CB2, M2 macrophages and the development of fibrosis. In a study to evaluate the protective effects of cannabinoids against neuroinflammation using a murine controlled cortical impact model of traumatic brain injury, Braun et al. (2018) observed a significant upregulation of CB2 receptor within infiltrating myeloid cells after 72 hours. The team also observed that selective activation of CB2 inhibited M1 polarisation and reduced cerebral oedema. Administration of a CB2 receptor antagonist effectively reversed CB2-mediated neuroprotection and worsened outcomes (Braun et al., 2018).
In psoriasis, the administration of Δ9-THC and CBD inhibit the proliferation of keratinocyte and modulate associated inflammation by promoting the conversion of Th1 lymphocytes to the anti-inflammatory Th2 phenotype (Sheriff et al., 2019). These effects, however, are independent of CB receptors, and appears to be mediated predominantly by PPARγ (Wilkinson and Williamson, 2007). Arachidonoyl-chloro-ethanolamide, a synthetic CB1agonist, decreases both keratinocyte cell proliferation in situin human skin cultures, and the expression of K6 and K16 in organ cultured human skin samples (Ramot et al., 2013). In a patent (20190060250) filed for psoriasis treatment with topical CBD and cannabigerol, it was showed that these phytocannabinoids dose-dependently inhibits the disease course via the restoration of balance between pro-inflammatory Th1 and anti-inflammatory Th2, and also through the inhibition of inflammatory cytokines and angiogenic growth factors (Changoer and Anastassov, 2019).
Inflammation in localised scleroderma, caused by excessive deposition of collagen, displays a particular profile of reduced Treg function, decreased Th17-derived cytokines such as IL-17, IL, 22 and IL-23, and increased chemokine (C-X-C motif) ligands 9 and 10 (Du et al., 2019). VCE-004.8, a synthetic cannabinoid, has been shown to reduce vascular collagen deposits and prevent macrophage infiltration and fibroblast migration in mouse models of scleroderma. Activation of CB2 appears to mediate the anti-inflammatory component of macrophage infiltration and IL-β secretion. Through interaction with Smads, PPARγ inhibits TGF-β production, accounting for the antifibrotic effects of VCE-004.8 (del Rio et al., 2016). Another synthetic non-psychoactive CB2 receptor agonist useful in the treatment of scleroderma is ajulemic acid (Burstein, 2018). Evidence from preclinical studies, and Phase 1 and 2 clinical trials shows that anabasum, a synthetic analog of Δ8-THC-11-oic acid, is a useful alternative in treating scleroderma (Man et al., 2017; Spiera et al., 2017;). Analysing skin biopsies from patients enrolled in these trials revealed that, ajulemic acid decreases inflammation-related genes and extracellular matrix-related genes important for fibrosis, and increases lipid-metabolising genes relevant for the production of pro-resolving eicosanoids (Martyanov et al., 2017).
Not only are topical phytocannabinoids effective in the management of psoriasis, they are effective in decreasing erythema and skin sebum as shown in pre-clinical mouse model of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced erythema and human trials involving topical application for 12 weeks (Ali and Akhtar, 2015; Dobrosi et al., 2008). Phytocannabinoids safely inhibits the production of sebum and the proliferation of sebocytes and reduce the expression of pro-inflammatory cytokines (Oláh et al., 2016). As observed in psoriasis, the positive effects of cannabinoids appear to be independent of CB receptor activation. For instance, CBD decreases sebum secretion and the proliferation sebocytes through the activation of TRPV1, 3 and 4 activation (Oláh et al., 2014). The anti-inflammatory effects appear to be dependent on A2A adenosine receptor activation, thus the inhibition of the p65 NF-κB pathway upon administration (De Petrocellis et al., 2012). Similar to CBD, cannabichromene and Δ9-tetrahydrocannabivarin, inhibits excessive sebaceous lipid production and decreases inflammation in SZ95 sebocytes. These non-psychotropic cannabinoids significantly inhibited arachidonic acid-induced acne-like lipogenesis, thus may show significant potential for use as novel agents in acne treatment. In contrast, CBG and cannabigerovarin increase sebaceous lipid synthesis, despite their ability to significantly inhibit inflammation. CBG and cannabigerovarin may therefore be useful in the treatment of dry-skin syndrome (Oláh et al., 2016).
Inflammation associated with dermatomyositis is driven by the activation of lymphocytes and dendritic cells which increases the production of IFNs and complement factors. This subsequently results in inflammatory myopathy, characterised by typical muscle tissue necrosis and regeneration, and may also lead to vasculopathy (Volc-Platzer, 2015). Administration of the CB2 receptor agonists decreases pro-inflammatory cytokine release such as TNF-α, and also the production of IFN-α and IFN-β (Scheau et al., 2020). In a study by Chen et al. (2017), it was identified that lenabasum, a CB2 receptor agonist, decreases CD4 cell populations and downregulates type 1 and 2 IFN activities in lesional dermatomyositis skin. In addition, CB2 receptor agonists have been shown to be safe, tolerable, and efficient thus represents a useful alternate in the treatment of inflammatory skin conditions (Scheau et al., 2020).
Cannabinoid receptor signaling is also implicated in the complex role of inflammation in carcinogenesis. Both the endocannabinoid system and exogenous cannabinoids attenuate inflammation associated with certain skin cancers such as melanoma, squamous cell and basal carcinomas and Kaposi sarcoma (Scheau et al., 2020). In summary, cannabinoids inhibit inflammatory processes associated with skin cancers by inhibiting TGF-β-mediated immunosuppression and tumor growth, TNF-α-mediated cell survival and proliferation, matrix metalloproteinase-mediated enhancement of epithelial–mesenchymal transition and the release of several other mediators of inflammation capable of fuelling carcinogenesis (Candido and Hagemann, 2013; Scheau et al., 2019; Cioni et al., 2019).