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).