Abstract
Cannabis use is an emergent risk factor for periodontitis, a chronic bacterial-induced disease of the supporting structures of the teeth. However, the mechanisms by which marijuana exposure predisposes to periodontal tissue destruction have yet to be elucidated. Therefore, we examined the influence of physiologically relevant doses of major marijuana-derived phytocannabinoid subtypes (cannabidiol [CBD]; cannabinol [CBN]; and tetrahydrocannabinol [THC], 1.0 μg/ml) on the interactions of three ultrastructurally variant oral pathogens, Porphyromonas gingivalis, Filifactor alocis, and Treponema denticola with the immune system. CBD, CBN, and THC each suppressed P. gingivalis-induced IL-12 p40, IL-6, IL-8, and TNF release while enhancing the anti-inflammatory cytokine, IL-10, from human innate cells. Similar phenomena were observed in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. Higher phytocannabinoid doses (≥5.0 μg/ml) compromised innate cell viability and inhibited the growth of P. gingivalis and F. alocis, relative to unexposed bacteria. T. denticola, however, was resistant to all cannabinoid doses tested (up to 10.0 μg/ml). Pharmaceutical inhibition and efficient gene silencing indicated that a common CB2/PI3K axis of immune suppression is triggered by phytocannabinoids in vitro. This pathway does not appear to perpetuate through the canonical GSK3β-dependent cholinergic anti-inflammatory pathway, the predominant endogenous inflammatory control system. In a repetitive, transient oral infection model, CBD also suppressed P. gingivalis-induced innate immune markers in wild-type mice, but not in CB2−/− mice. If such phenomena occur in humans in situ, environmental cannabinoids may enhance periodontitis via direct toxic effects on specific oral bacteria; by compromising innate cell vitality; and/or through a suppressed innate response to periodontal pathogens involving a CB2/PI3K signaling lineage.
Highlights
While Osola et al have suggested that the cannabinoid receptor 2 (CB2) agonist, HU-308 is osteoprotective in an LPS-induced oral inflammation model in rats [16], other studies suggest that cannabinoids may predispose animals to destructive periodontal disease
P. gingivalis is the archetypal Gram-negative, anaerobic periodontal pathogen that has been associated with several systemic sequelae of periodontitis, including poor pregnancy outcome, cardiovascular complications, Alzheimer’s disease and, as we have recently shown, esophageal cancer [22,23,24,25,26]
Having established that CBD, CBN, and THC each subdue pro-inflammatory cytokine release from monocytes and telomerase-immortalized gingival keratinocytes (TIGKs) cells exposed to oral bacteria, we examined the relative contributions of the cannabinoid receptors CB1 and CB2 to this immunosuppressive phenomenon
Summary
Tobacco-independent relative risk for marijuana use has been estimated at between 1.6 and 3.1, depending on the disease severity threshold assessed, which is similar to tobacco smoke itself [5, 8, 12]. Destructive periodontal diseases in marijuana users may onset at an earlier age than seen in the general periodontitis population, who do not normally develop periodontitis until middle age [6,7,8, 11,12,13]. While Osola et al have suggested that the CB2 agonist, HU-308 is osteoprotective in an LPS-induced oral inflammation model in rats [16], other studies suggest that cannabinoids may predispose animals to destructive periodontal disease. The mechanisms underlying predisposition to destructive periodontal disease due to marijuana exposure are unclear, cannabis has long been ascribed anti-inflammatory properties
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