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

Autor:	Meghil MM; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States.; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia at Augusta University, Augusta, GA, United States., Tawfik OK; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States., Elashiry M; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States.; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia at Augusta University, Augusta, GA, United States., Rajendran M; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States., Arce RM; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States., Fulton DJ; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, United States., Schoenlein PV; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States., Cutler CW; Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2019 Sep 24; Vol. 10, pp. 2286. Date of Electronic Publication: 2019 Sep 24 (Print Publication: 2019).
DOI:	10.3389/fimmu.2019.02286
Abstrakt:	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. (Copyright © 2019 Meghil, Tawfik, Elashiry, Rajendran, Arce, Fulton, Schoenlein and Cutler.)
Databáze:	MEDLINE
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