title: Manipulation of necroptosis by Porphyromonas gingivalis in periodontitis development.
abstract: To eliminate invading pathogens and keep homeostasis, host employs multiple approaches such as the non-inflammation associated-apoptosis, inflammation associated-necroptosis and pyroptosis, etc. Necroptosis is known as a highly pro-inflammatory form of cell death due to the release of massive damage-associated molecular patterns (DAMPs). For the first time, we reported that Porphyromonas gingivalis induced cellular necroptosis through receptor-interacting protein 1 (RIP1)/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway in monocytes. Necroptosis in THP-1 cells was induced by MLKL phosphorylation in vitro. P. gingivalis treated-THP-1 cells exhibited lower cell death rate with pretreatment of inhibitors RIP1 and MLKL, accompanied with attenuated TNF-α and IL-6 expressions. Moreover, the necroptosis risk was also reduced via gene silencing by RIP3 or MLKL in the P. gingivalis treated-THP-1 cell lines. We further explored P. gingivalis-induced necroptosis in animal models in vivo. Firstly, C57BL/6 mice were injected with P. gingivalis in the subcutaneous chamber model. Animals pretreated with MLKL inhibitor exhibited significantly enhanced P. gingivalis clearance; in addition, levels of TNF-α and IL-6 were notably decreased by 60% via MLKL inhibition. Secondly, P. gingivalis-induced periodontitis was utilized to investigate necroptosis related-periodontopathogensis. Positive staining of phosphorylated MLKL in mice periodontitis biopsies was detected to a higher degree, while larger amount of alveolar bone loss was observed in MLKL (-) group comparing to those in the MLKL (+) group. These findings may suggest that P. gingivalis play essential roles in necroptosis process during periodontitis, and our research may shed light on the further work on the related periodontopathogenesis investigation.
authors.affiliation: Nanjing Stomatological Hospital, Medical School of Nanjing University, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ke
authors.affiliation: Nanjing Stomatological Hospital, Medical School of Nanjing University, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Lei
authors.affiliation: Nanjing Stomatological Hospital, Medical School of Nanjing University, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Li
authors.affiliation: Nanjing Stomatological Hospital, Medical School of Nanjing University, China. Electronic address: lihouxuan3435_0@163.com.
authors.forename: Houxuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Nanjing Stomatological Hospital, Medical School of Nanjing University, China. Electronic address: yanfh@nju.edu.cn.
authors.forename: Fuhua
authors.initials: F
authors.lastname: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016866:Bacteroidaceae Infections / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010518:Periodontitis / Q000276:immunology / Q000473:pathology*; D016966:Porphyromonas gingivalis; D011494:Protein Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: C570693:MLKL protein, human; C570694:MLKL protein, mouse; D011494:Protein Kinases
keywords: Necroptosis; Periodontitis; Porphyromonas gingivalis; Receptor-interacting protein