Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation

Pachiappan Arjunan, Mohamed M. Meghil, Wenhu Pi, Jinxian Xu, Liwei Lang, Ahmed El-Awady, William Sullivan, Mythilypriya Rajendran, Mariana Sousa Rabelo, Tong Wang, Omnia K. Tawfik, Govindarajan Kunde-Ramamoorthy, Nagendra Singh, Muthusamy Thangaraju, Cristiano Susin, Yong Teng, Roger Mauricio Arce Munoz, Christopher W Cutler

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.

Original languageEnglish (US)
Article number16607
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Porphyromonas gingivalis
Squamous Cell Carcinoma
Chronic Periodontitis
Cell Proliferation
Dendritic Cells
Angiogenic Proteins
Periodontitis
Mouth Neoplasms
Gingiva
Tumor Biomarkers
Coculture Techniques
Immunosuppression
Monocytes
Ligands
Biopsy
Infection
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

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Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation. / Arjunan, Pachiappan; Meghil, Mohamed M.; Pi, Wenhu; Xu, Jinxian; Lang, Liwei; El-Awady, Ahmed; Sullivan, William; Rajendran, Mythilypriya; Rabelo, Mariana Sousa; Wang, Tong; Tawfik, Omnia K.; Kunde-Ramamoorthy, Govindarajan; Singh, Nagendra; Thangaraju, Muthusamy; Susin, Cristiano; Teng, Yong; Arce Munoz, Roger Mauricio; Cutler, Christopher W.

In: Scientific Reports, Vol. 8, No. 1, 16607, 01.12.2018.

Research output: Contribution to journalArticle

Arjunan, P, Meghil, MM, Pi, W, Xu, J, Lang, L, El-Awady, A, Sullivan, W, Rajendran, M, Rabelo, MS, Wang, T, Tawfik, OK, Kunde-Ramamoorthy, G, Singh, N, Thangaraju, M, Susin, C, Teng, Y, Arce Munoz, RM & Cutler, CW 2018, 'Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation', Scientific Reports, vol. 8, no. 1, 16607. https://doi.org/10.1038/s41598-018-35126-8
Arjunan, Pachiappan ; Meghil, Mohamed M. ; Pi, Wenhu ; Xu, Jinxian ; Lang, Liwei ; El-Awady, Ahmed ; Sullivan, William ; Rajendran, Mythilypriya ; Rabelo, Mariana Sousa ; Wang, Tong ; Tawfik, Omnia K. ; Kunde-Ramamoorthy, Govindarajan ; Singh, Nagendra ; Thangaraju, Muthusamy ; Susin, Cristiano ; Teng, Yong ; Arce Munoz, Roger Mauricio ; Cutler, Christopher W. / Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.",
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AU - Arjunan, Pachiappan

AU - Meghil, Mohamed M.

AU - Pi, Wenhu

AU - Xu, Jinxian

AU - Lang, Liwei

AU - El-Awady, Ahmed

AU - Sullivan, William

AU - Rajendran, Mythilypriya

AU - Rabelo, Mariana Sousa

AU - Wang, Tong

AU - Tawfik, Omnia K.

AU - Kunde-Ramamoorthy, Govindarajan

AU - Singh, Nagendra

AU - Thangaraju, Muthusamy

AU - Susin, Cristiano

AU - Teng, Yong

AU - Arce Munoz, Roger Mauricio

AU - Cutler, Christopher W

PY - 2018/12/1

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N2 - Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.

AB - Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.

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