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Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis

As fundamental processes of immune homeostasis, autophagy, and apoptosis must be maintained to mitigate risk of chronic inflammation and autoimmune diseases. Periodontitis is a chronic inflammatory disease characterized by oral microbial dysbiosis, and dysregulation of dendritic cell (DC) and T cell...

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Autores principales: Meghil, Mohamed M., Tawfik, Omnia K., Elashiry, Mahmoud, Rajendran, Mythilypriya, Arce, Roger M., Fulton, David J., Schoenlein, Patricia V., Cutler, Christopher W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769118/
https://www.ncbi.nlm.nih.gov/pubmed/31608069
http://dx.doi.org/10.3389/fimmu.2019.02286
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author Meghil, Mohamed M.
Tawfik, Omnia K.
Elashiry, Mahmoud
Rajendran, Mythilypriya
Arce, Roger M.
Fulton, David J.
Schoenlein, Patricia V.
Cutler, Christopher W.
author_facet Meghil, Mohamed M.
Tawfik, Omnia K.
Elashiry, Mahmoud
Rajendran, Mythilypriya
Arce, Roger M.
Fulton, David J.
Schoenlein, Patricia V.
Cutler, Christopher W.
author_sort Meghil, Mohamed M.
collection PubMed
description As fundamental processes of immune homeostasis, autophagy, and apoptosis must be maintained to mitigate risk of chronic inflammation and autoimmune diseases. Periodontitis is a chronic inflammatory disease characterized by oral microbial dysbiosis, and dysregulation of dendritic cell (DC) and T cell responses. The aim of this study was to elucidate the underlying mechanisms by which the oral microbe Porphyromonas gingivalis (P. gingivalis) manipulates dendritic cell signaling to perturb both autophagy and apoptosis. Using a combination of Western blotting, flow cytometry, qRT-PCR and immunofluorescence analysis, we show a pivotal role for the minor (Mfa1) fimbriae of P. gingivalis in nuclear/cytoplasmic shuttling of Akt and FOXO1 in human monocyte-derived DCs. Mfa1-induced Akt nuclear localization and activation ultimately induced mTOR. Activation of the Akt/mTOR axis downregulated intracellular LC3II, also known as Atg8, required for autophagosome formation and maturation. Use of allosteric panAkt inhibitor MK2206 and mTOR inhibitor rapamycin confirmed the role of Akt/mTOR signaling in autophagy inhibition by P. gingivalis in DCs. Interestingly, this pathway was also linked to induction of the anti-apoptotic protein Bcl2, decreased caspase-3 cleavage and decreased expression of pro-apoptotic proteins Bax and Bim, thus promoting longevity of host DCs. Addition of ABT-199 peptide to disrupt the interaction of antiapoptotic Bcl2 and its proapoptotic partners BAK/BAX restored apoptotic death to P. gingivalis-infected DC cells. In summary, we have identified the underlying mechanism by which P. gingivalis promotes its own survival and that of its host DCs.
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spelling pubmed-67691182019-10-11 Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis Meghil, Mohamed M. Tawfik, Omnia K. Elashiry, Mahmoud Rajendran, Mythilypriya Arce, Roger M. Fulton, David J. Schoenlein, Patricia V. Cutler, Christopher W. Front Immunol Immunology As fundamental processes of immune homeostasis, autophagy, and apoptosis must be maintained to mitigate risk of chronic inflammation and autoimmune diseases. Periodontitis is a chronic inflammatory disease characterized by oral microbial dysbiosis, and dysregulation of dendritic cell (DC) and T cell responses. The aim of this study was to elucidate the underlying mechanisms by which the oral microbe Porphyromonas gingivalis (P. gingivalis) manipulates dendritic cell signaling to perturb both autophagy and apoptosis. Using a combination of Western blotting, flow cytometry, qRT-PCR and immunofluorescence analysis, we show a pivotal role for the minor (Mfa1) fimbriae of P. gingivalis in nuclear/cytoplasmic shuttling of Akt and FOXO1 in human monocyte-derived DCs. Mfa1-induced Akt nuclear localization and activation ultimately induced mTOR. Activation of the Akt/mTOR axis downregulated intracellular LC3II, also known as Atg8, required for autophagosome formation and maturation. Use of allosteric panAkt inhibitor MK2206 and mTOR inhibitor rapamycin confirmed the role of Akt/mTOR signaling in autophagy inhibition by P. gingivalis in DCs. Interestingly, this pathway was also linked to induction of the anti-apoptotic protein Bcl2, decreased caspase-3 cleavage and decreased expression of pro-apoptotic proteins Bax and Bim, thus promoting longevity of host DCs. Addition of ABT-199 peptide to disrupt the interaction of antiapoptotic Bcl2 and its proapoptotic partners BAK/BAX restored apoptotic death to P. gingivalis-infected DC cells. In summary, we have identified the underlying mechanism by which P. gingivalis promotes its own survival and that of its host DCs. Frontiers Media S.A. 2019-09-24 /pmc/articles/PMC6769118/ /pubmed/31608069 http://dx.doi.org/10.3389/fimmu.2019.02286 Text en Copyright © 2019 Meghil, Tawfik, Elashiry, Rajendran, Arce, Fulton, Schoenlein and Cutler. 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
Meghil, Mohamed M.
Tawfik, Omnia K.
Elashiry, Mahmoud
Rajendran, Mythilypriya
Arce, Roger M.
Fulton, David J.
Schoenlein, Patricia V.
Cutler, Christopher W.
Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title_full Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title_fullStr Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title_full_unstemmed Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title_short Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis
title_sort disruption of immune homeostasis in human dendritic cells via regulation of autophagy and apoptosis by porphyromonas gingivalis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769118/
https://www.ncbi.nlm.nih.gov/pubmed/31608069
http://dx.doi.org/10.3389/fimmu.2019.02286
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