Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens

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.

Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma

“…A limitation of this study is that we only assessed one of the chemotherapies used in medulloblastoma treatment and have not investigated the influence that THC or CBD may have on other standard agents used in medulloblastoma or ependymoma, such as cisplatin, vincristine, etoposide, or radiation. It has been shown that phytocannabinoids have suppressive effects on immune cells [ 67 ]; however another limitation of our research is that we evaluated the effectiveness of THC and CBD using human brain cancer cells xenografted into immune-deficient mice. While preclinical studies that showed cannabinoids are effective against adult glioblastoma used similar immune-deficient models, it may be useful to determine if the presence of a functioning immune system might alter the effects of cannabinoids on medulloblastoma and ependymoma.…”

Cannabis, the Endocannabinoid System and Immunity—the Journey from the Bedside to the Bench and Back

“…The same group also investigated the effects of THC and Cannabis extracts on host resistance to Listeria, monocytogenes, and herpes simplex virus [ 60 ]. Compromised resistance to different pathogens was demonstrated during the following years [ 61 , 62 , 63 , 64 ]. Later on, the roles of the endocannabinoid system in the induction of immunity by bacterial pathogens were established [ 65 ] and specific CB2 genotypes were found to correlate with susceptibility to some viral diseases [ 36 , 66 , 67 ].…”

Cannabinoids in Medicine: Cancer, Immunity, and Microbial Diseases

“…An association has been reported between CBR2 expression level, cell activation, and the presence of immune modulators [ 85 ]. Inhibition of CBR2 with JTE907 acting as a selective CBR2 inverse agonist with combined CBR1 / CBR2 gene silencing, showed that CBR2 (not CBR1) is responsible for phytocannabinoid-mediated immune suppression [ 86 ]. CBR2 suppresses T cell immune responses in T cell-mediated diseases and at the same time positively regulates T-independent immune responses.…”