Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation

Abstract

Cannabinoid receptors (CBR) 1 and 2 have been implicated in keratinocyte differentiation/proliferation. How CB receptors affect epidermal permeability barrier and stratum corneum structure and function remains unclear. Permeability barrier abrogation was induced by sequential tape-stripping of the SC and assessed in both CB1R and CB2R knockout (-/-) mice in comparison with wild-type (+/+) littermates. Absence of CB1R delays permeability barrier recovery, while the latter was found to be accelerated in CB2R -/- mice. While increased lamellar body (LB) secretion is observed in CB2R -/- mice accounting for the enhanced recovery, CB1R -/- animals display strong alterations in lipid bilayer structures. Markers for epidermal differentiation (i.e. filaggrin, loricrin and involucrin) and terminal differentiation (i.e. TUNEL assay and caspase-14 activation) were respectively decreased and increased in CB1R and CB2R -/- mice. Surprisingly, CB1R agonist treatment of human cultured keratinocytes increases mRNA of p21 and cytokeratin 1 and 10 and decreases cyclin D1 but protein levels remained unchanged. Such paradox could partially be explained by the increase in non-phosphorylated-4E-BP1, an inhibitor of mRNA translation, following CB1R agonist treatment. Altogether, these observations put forward the importance and the complexity of cannabinoid signalling for the regulation of permeability barrier and epidermal differentiation.

Epigenetic control of skin differentiation genes by phytocannabinoids

“…On the one hand, it can be proposed that knock-out animals might have developed different compensatory mechanisms that do not fully reflect the physiology of normal (wild-type) keratinocytes. On the other hand, the opposite effects of arachidonoylcyclopropylamide on human keratinocytes (so called 'cannabinoid paradox') at doses well above those used here might be due to complex mechanisms, which may be related to eCBs signalling mechanisms that inhibit mRNA translation (Roelandt et al, 2012), as well as to reduced cell viability and proliferation induced by eCBs and phytocannabinoids at concentrations >1 μM (Siegmund et al, 2006;Wilkinson and Williamson, 2007;Pucci et al, 2011;Tóth et al, 2011). At any rate, consistent with our previous findings with AEA (Paradisi et al, 2008), here we show that changes in K10 gene expression induced by CBD, but not CBG, are due to increased methylation of genomic DNA.…”

“…It should also be noted that recent findings have shown that the barrier recovery is delayed in CB 1 knockout mice, while it is accelerated in CB2 knock-out mice (Roelandt et al, 2012). Additionally, CB1 activation in human keratinocytes by high doses (2.5 and 10 μM) of arachidonoylcyclopropylamide for 24 h increased the mRNA level of K10 at high Ca 2+ concentrations, while reducing K10 protein level under the same conditions (Roelandt et al, 2012). On the one hand, it can be proposed that knock-out animals might have developed different compensatory mechanisms that do not fully reflect the physiology of normal (wild-type) keratinocytes.…”

“…In this context, it should be mentioned that SR141716 also behaves as an agonist at GPR55 (Kapur et al, 2009), although there are no data on a possible involvement of this receptor in the epidermis. It should also be noted that recent findings have shown that the barrier recovery is delayed in CB 1 knockout mice, while it is accelerated in CB2 knock-out mice (Roelandt et al, 2012). Additionally, CB1 activation in human keratinocytes by high doses (2.5 and 10 μM) of arachidonoylcyclopropylamide for 24 h increased the mRNA level of K10 at high Ca 2+ concentrations, while reducing K10 protein level under the same conditions (Roelandt et al, 2012).…”

Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing

“…CB 2 receptor activation also attenuates pathological liver fibrosis in mice (Guillot et al, 2014;Mahmoud et al, 2014;Munoz-Luque et al, 2008), and exerts antifibrotic effect in bleomycin-induced dermal fibrosis (Akhmetshina et al, 2009). In addition, absence of CB 2 receptor improves keratinocyte differentiation and decreases proliferation in a tapestripping-induced epidermal barrier abrogation model (Roelandt et al, 2012).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…CB1 controls melanogenesis in epidermal melanocytes too (696), possibly also through intercellular communication mechanisms involving the keratinocytes (516). Interestingly, in mice, genetic ablation of CB1 delays, whereas lack of CB2 accelerates, recovery of the epidermal permeability barrier, which is keratinocyte proliferation and differentiation dependent (738). Furthermore, CB1 signaling inhibits human hair elongation, whereas CB2 stimulates lipogenesis in human sebaceous gland-derived sebocytes (70).…”