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

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...

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Autores principales: Gu, Zhen, Singh, Shilpa, Niyogi, Rajarshi G., Lamont, Gwyneth J., Wang, Huizhi, Lamont, Richard J., Scott, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804395/
https://www.ncbi.nlm.nih.gov/pubmed/31681262
http://dx.doi.org/10.3389/fimmu.2019.02288
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author Gu, Zhen
Singh, Shilpa
Niyogi, Rajarshi G.
Lamont, Gwyneth J.
Wang, Huizhi
Lamont, Richard J.
Scott, David A.
author_facet Gu, Zhen
Singh, Shilpa
Niyogi, Rajarshi G.
Lamont, Gwyneth J.
Wang, Huizhi
Lamont, Richard J.
Scott, David A.
author_sort Gu, Zhen
collection PubMed
description 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.
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spelling pubmed-68043952019-11-03 Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens Gu, Zhen Singh, Shilpa Niyogi, Rajarshi G. Lamont, Gwyneth J. Wang, Huizhi Lamont, Richard J. Scott, David A. Front Immunol Immunology 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. Frontiers Media S.A. 2019-10-15 /pmc/articles/PMC6804395/ /pubmed/31681262 http://dx.doi.org/10.3389/fimmu.2019.02288 Text en Copyright © 2019 Gu, Singh, Niyogi, Lamont, Wang, Lamont and Scott. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Gu, Zhen
Singh, Shilpa
Niyogi, Rajarshi G.
Lamont, Gwyneth J.
Wang, Huizhi
Lamont, Richard J.
Scott, David A.
Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title_full Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title_fullStr Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title_full_unstemmed Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title_short Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens
title_sort marijuana-derived cannabinoids trigger a cb2/pi3k axis of suppression of the innate response to oral pathogens
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804395/
https://www.ncbi.nlm.nih.gov/pubmed/31681262
http://dx.doi.org/10.3389/fimmu.2019.02288
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