A dysbiotic microbiome triggers T
            <sub>H</sub>
            17 cells to mediate oral mucosal immunopathology in mice and humans

Dutzan, Nicolás; Kajikawa, Tetsuhiro; Abusleme, Loreto; Greenwell-Wild, Teresa; Zuazo, Carlos E.; Ikeuchi, Tomoko; Brenchley, Laurie; Abe, Toshiharu; Hurabielle, Charlotte; Martin, Daniel; Morell, Robert J.; Freeman, Alexandra F.; Lazarevic, Vanja; Trinchieri, Giorgio; Diaz, Patricia I.; Holland, Steven M.; Belkaid, Yasmine; Hajishengallis, George; Moutsopoulos, Niki M.

doi:10.1126/scitranslmed.aat0797

Cited by 287 publications

(377 citation statements)

References 60 publications

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“…Notably, the advantage of GS‐9973 treatment is that it shows suppressive effect in bone loss even when administered after periodontitis induction, suggesting that the SYK inhibitor may be able to slow down progressive bone loss in human periodontitis. This is different from anti‐IL‐17A antibody administration in the same periodontitis model . The SYK inhibitor treatment may meet the requirements of clinical practice because intragingival injection, which would allow to reduce the dose and frequency of SYK inhibitor administration and lessen the risk for potential adverse events, could be considered as a route for administration in humans.…”

Section: Discussionmentioning

confidence: 99%

“…The SYK inhibitor treatment may meet the requirements of clinical practice because intragingival injection, which would allow to reduce the dose and frequency of SYK inhibitor administration and lessen the risk for potential adverse events, could be considered as a route for administration in humans. Recent investigations demonstrated that T H 17 cells that produce IL‐17A and IL‐17F are the primary drivers for the pathogenesis of periodontitis in mice and humans . These studies provided mechanistic and genetic justification that inhibition of IL‐17 family members or suppression of T H 17 cell development may be a plausible therapeutic option for treatment of alveolar bone resorption in periodontitis.…”

Section: Discussionmentioning

confidence: 99%

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Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 −/− ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% AE 10.2%; female 19.0% AE 6.0%) compared with wild-type control mice (male 25.3% AE 5.8%; female 30.8% AE 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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“…For example, patients with mutations that disrupt interleukin‐17 signaling are prone to fungal infection . Interleukin‐17 receptor A null mice are more susceptible to oropharyngeal candidiasis caused by the commensal fungus Candida albicans than T helper 1‐deficient mice . However, exaggerated production of interleukin‐17 was also found in gingival tissues affected by periodontitis .…”

Section: Findings Of Transcriptome Studies In Gingivitis and Periodonmentioning

confidence: 99%

Periodontal inflammation: Integrating genes and dysbiosis

Zhang

Yu²,

Arce

2019

Periodontology 2000

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Biofilm bacteria co‐evolve and reach a symbiosis with the host on the gingival surface. The disruption of the homeostatic relationship between plaque bacteria and the host can initiate and promote periodontal disease progression. Recent advances in sequencing technologies allow researchers to profile disease‐associated microbial communities and quantify microbial metabolic activities and host transcriptional responses. In addition to confirming the findings from previous studies, new putative pathogens and novel genes that have not previously been associated with periodontitis, emerge. For example, multiple studies have reported that Synergistetes bacteria are associated with periodontitis. Genes involved in epithelial barrier defense were downregulated in periodontitis, while excessive expression of interleukin‐17 was associated with a hyperinflammatory response in periodontitis and with a unique microbial community. Bioinformatics‐enabled gene ontology pathway analyses provide a panoramic view of the bacterial and host activities as they shift from periodontal health to disease. Additionally, host innate factors, such as genetic variants identified by either a candidate‐gene approach or genome‐wide association analyses, have an impact on subgingival bacterial colonization. Transgenic mice carrying candidate genetic variants, or with the deletion of candidate genes mimicking the deleterious loss‐of‐function variant effect, provide experimental evidence validating the biologic relevance of the novel markers associated with the microbial phenotype identified through a statistical approach. Further refinement in bioinformatics, data management approaches, or statistical tools, are required to gain insight into host‐microbe interactions by harmonizing the multidimensional “big” data at the genomic, transcriptional, and proteomic levels.

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“…Periodontitis results from polymicrobial synergy and dysbiosis; however, periodontal tissue breakdown is mainly determined by the host's immune response, where the T‐lymphocyte subpopulations play a central role in the alveolar bone resorption that leads to tooth loss . In this context, T‐helper (Th)1 and Th17 lymphocytes have been related more to destructive events of periodontitis, while Th2 and T regulatory (Treg) lymphocytes have been related more to the suppression of the Th1 and Th17 responses, periodontitis remission, and periodontal healing …”

Section: Introductionmentioning

confidence: 99%

IL‐22–expressing CD4⁺AhR⁺ T lymphocytes are associated with RANKL‐mediated alveolar bone resorption during experimental periodontitis

Monasterio

Budini

Fernández

et al. 2019

J of Periodontal Research

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Background and Objective Over the past few years, the importance of interleukin‐22 (IL‐22) and T‐helper (Th)22 lymphocytes in the pathogenesis of periodontitis has become apparent; however, there are still aspects that are not addressed yet. Cells expressing IL‐22 and aryl hydrocarbon receptor (AhR), transcription factor master switch gene implicated in the differentiation and function of Th22 lymphocytes, have been detected in periodontal tissues of periodontitis‐affected patients. In addition, IL‐22 has been associated with osteoclast differentiation and their bone resorptive activity in vitro. However, the destructive potential of IL‐22–expressing AhR+ Th22 lymphocytes over periodontal tissues during periodontitis has not been demonstrated in vivo yet. Therefore, this study aimed to analyze whether IL‐22–expressing CD4+AhR+ T lymphocytes detected in periodontal lesions are associated with alveolar bone resorption during experimental periodontitis. Material and Methods Using a murine model of periodontitis, the expression levels of IL‐22 and AhR, as well as the Th1‐, Th2‐, Th17‐ and T regulatory‐associated cytokines, were analyzed in periodontal lesions using qPCR. The detection of CD4+IL‐22+AhR+ T lymphocytes was analyzed in periodontal lesions and cervical lymph nodes that drain these periodontal lesions using flow cytometry. In addition, the expression of the osteoclastogenic mediator called receptor activator of nuclear factor‐κB ligand (RANKL) was analyzed by qPCR, western blot, and immunohistochemistry. Finally, alveolar bone resorption was analyzed using micro‐computed tomography and scanning electron microscopy, and the bone resorption levels were correlated with IL‐22 and RANKL expression. Results Higher levels of IL‐22, AhR, and RANKL, as well as IL‐1β, IL‐6, IL‐12, IL‐17, IL‐23, and TNF‐α, were expressed in periodontal lesions of infected mice compared with periodontal tissues of sham‐infected and non‐infected controls. Similarly, high RANKL immunoreaction was observed in periodontal tissues of infected mice; however, few or absent RANKL immunoreaction was observed in controls. This association between RANKL and periodontal infection was ratified by western blot. Furthermore, a higher detection of CD4+IL‐22+AhR+ T lymphocytes was found in periodontal lesions and cervical lymph nodes that drain these periodontal lesions in infected mice compared with non‐infected controls. Finally, the increased IL‐22 and RANKL expression showed positive correlation between them and with the augmented alveolar bone resorption observed in experimental periodontal lesions. Conclusion This study demonstrates the increase of IL‐22–expressing CD4+AhR+ T lymphocytes in periodontitis‐affected tissues and shows a positive correlation between IL‐22, RANKL expression, and alveolar bone resorption.

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A dysbiotic microbiome triggers T _H 17 cells to mediate oral mucosal immunopathology in mice and humans

Abstract: One Sentence Summary: Combined human and animal model studies conclusively implicate microbiota-triggered oral mucosal Th17 cells as drivers of local immunopathology and therapeutic targets in periodontitis.

Cited by 287 publications

References 60 publications

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Periodontal inflammation: Integrating genes and dysbiosis

IL‐22–expressing CD4⁺AhR⁺ T lymphocytes are associated with RANKL‐mediated alveolar bone resorption during experimental periodontitis

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A dysbiotic microbiome triggers T H 17 cells to mediate oral mucosal immunopathology in mice and humans

Abstract: One Sentence Summary: Combined human and animal model studies conclusively implicate microbiota-triggered oral mucosal Th17 cells as drivers of local immunopathology and therapeutic targets in periodontitis.

Cited by 287 publications

References 60 publications

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Periodontal inflammation: Integrating genes and dysbiosis

IL‐22–expressing CD4+AhR+ T lymphocytes are associated with RANKL‐mediated alveolar bone resorption during experimental periodontitis

Contact Info

Product

Resources

About

A dysbiotic microbiome triggers T _H 17 cells to mediate oral mucosal immunopathology in mice and humans

IL‐22–expressing CD4⁺AhR⁺ T lymphocytes are associated with RANKL‐mediated alveolar bone resorption during experimental periodontitis