The Th17/Treg cell balance: crosstalk among the immune system, bone and microbes in periodontitis

Graves²

2022

Front. Immunol.

Periodontitis involves the loss of connective tissue attachment and alveolar bone. Single cell RNA-seq experiments have provided new insight into how resident cells and infiltrating immune cells function in response to bacterial challenge in periodontal tissues. Periodontal disease is induced by a combined innate and adaptive immune response to bacterial dysbiosis that is initiated by resident cells including epithelial cells and fibroblasts, which recruit immune cells. Chemokines and cytokines stimulate recruitment of osteoclast precursors and osteoclastogenesis in response to TNF, IL-1β, IL-6, IL-17, RANKL and other factors. Inflammation also suppresses coupled bone formation to limit repair of osteolytic lesions. Bone lining cells, osteocytes and periodontal ligament cells play a key role in both processes. The periodontal ligament contains cells that exhibit similarities to tendon cells, osteoblast-lineage cells and mesenchymal stem cells. Bone lining cells consisting of mesenchymal stem cells, osteoprogenitors and osteoblasts are influenced by osteocytes and stimulate formation of osteoclast precursors through MCSF and RANKL, which directly induce osteoclastogenesis. Following bone resorption, factors are released from resorbed bone matrix and by osteoclasts and osteal macrophages that recruit osteoblast precursors to the resorbed bone surface. Osteoblast differentiation and coupled bone formation are regulated by multiple signaling pathways including Wnt, Notch, FGF, IGF-1, BMP, and Hedgehog pathways. Diabetes, cigarette smoking and aging enhance the pathologic processes to increase bone resorption and inhibit coupled bone formation to accelerate bone loss. Other bone pathologies such as rheumatoid arthritis, post-menopausal osteoporosis and bone unloading/disuse also affect osteoblast lineage cells and participate in formation of osteolytic lesions by promoting bone resorption and inhibiting coupled bone formation. Thus, periodontitis involves the activation of an inflammatory response that involves a large number of cells to stimulate bone resorption and limit osseous repair processes.

Section: Periodontal Diseasementioning

confidence: 99%

Impact of the host response and osteoblast lineage cells on periodontal disease

Graves²

2022

Front. Immunol.

“…Impaired bone repair and reconstruction in in amed periodontium remains a major clinical challenge for bone regeneration in periodontitis patients 31 . The imbalance between Th17 and Treg cells in periodontal tissue is closely related to the progression of in ammation 10 . An elevated Th17/Treg ratio in peripheral blood is also associated with periodontal in ammation and alveolar bone destruction 11,32 .…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, we found that IL-17 promoted bone resorption via osteocyte-speci c signaling pathways, and also regulated the osteogenesis of mesenchymal stem cells (MSCs) 7,8,9 . Conversely, Treg cells participate in immunosuppression and tissue repair to maintain periodontal health, depending on sustained high expression of FOXP3 and interleukin-10 (IL-10) 10 . Rather than in periodontal tissue, an elevated Th17/Treg ratio in peripheral blood without systemic diseases is also associated with periodontal in ammation and alveolar bone destruction 2,11 .…”

Section: Introductionmentioning

confidence: 99%

hBMSC-derived Exosomes Mitigate Th17/Treg Homeostasis in Periodontitis via miR-1246

Xia

Cheng

et al. 2022

Preprint

Background Chronic inflammatory bone loss in periodontitis is closely related to helper T cell 17 (Th17) / regulatory T cell (Treg) imbalance. The therapeutic function of mesenchymal stem cells is mainly attributed to the paracrine exosomes. We aimed to investigate the immunomodulatory effect of human bone marrow mesenchymal stem cells (hBMSC)-derived exosomes in Th17/Treg homeostasis in periodontitis. Methods Peripheral blood was collected from periodontitis patients or healthy donors. The level of Th17-related biomarker interleukin-17A (IL-17A) and Treg-related forkhead box protein 3 (FOXP3) was analyzed by ELISA, and mRNA expression level of RAR-related orphan receptor C (RORC) and FOXP3 was detected by qRT-PCR. Naïve CD4+ T cells extracted from the peripheral blood of periodontitis patients were co-cultured with hBMSC-derived exosomes from healthy subjects. The ratio of Th17/Treg was examined by flow cytometry and the expression of inflammatory cytokines was determined by qRT-PCR. In vivo, exosomes-loaded hydrogel was injected into periodontal pockets of mice with experimental periodontitis. The periodontal inflammation and bone regeneration was evaluated by histological staining, immunofluorescence staining and micro-CT. Furthermore, the differentially expressed miRNAs in exosomes stimulated by P.g. LPS were investigated by miRNA sequencing and bioinformatics analysis. The interaction between candidate miRNA and its target gene in CD4+ T cells was verified by dual luciferase activity assay. Lastly, the downstream Yes-related protein 1(YAP1)/Hippo pathway was evaluated by western blotting. Results The ratio of Th17/Treg is significantly increased in the peripheral blood of periodontitis patients. hBMSC-derived exosomes decreased Th17/Treg ratio in CD4+ T cells in vitro and ameliorated inflammation and bone loss in periodontitis mice. Mechanistically, the enrichment of miR-1246 in exosomes showed the enhanced effects of down-regulating Th17/Treg ratio, which could be reversed by miR-1246 inhibitor. Furthermore, exosomal miR-1246 suppressed the expression of the target protein angiotensin converting enzyme2 (ACE2) and upregulated the expression ratio P-YAP1/YAP1 in CD4+ T cells. Conclusions hBMSC-derived exosomes could alleviate periodontal inflammation through modulating the balance of Th17/Treg via targeting ACE2 and downregulating YAP1/Hippo signaling pathway, which shed light on a novel cell-free immunotherapy for periodontal regeneration.

“…By contrast, Treg is considered to play a protective role in periodontal tissue and can inhibit the differentiation of Th1, Th2, and Th17. Generally, Treg is regarded as an important cell in maintaining periodontal immune homeostasis 164–166 . The production of TGF‐β and T lymphocyte‐associated molecule 4 (cytotoxic T cell antigen 4) by Treg cells could diminish inflammatory responses, thus reduce the severity of periodontitis 167 …”

Section: Effects Of Immune Cells and Immune Senescence In Periodontitismentioning

confidence: 99%

“…Generally, Treg is regarded as an important cell in maintaining periodontal immune homeostasis. [164][165][166] The production of TGF-β and T lymphocyte-associated molecule 4 (cytotoxic T cell antigen 4) by Treg cells could diminish inflammatory responses, thus reduce the severity of periodontitis. 167…”

Section: Immune Functions Of T Cells In Periodontitismentioning

confidence: 99%

Immune senescence and periodontitis: From mechanism to therapy

Liu

Dan

Journal of Leukocyte Biology

et al. 2022

Periodontitis is one of the most prevalent infectious inflammatory diseases, characterized by irreversible destruction of the supporting tissues of teeth, which is correlated with a greater risk of multiple systemic diseases, thus regarded as a major health concern. Dysregulation between periodontal microbial community and host immunity is considered to be the leading cause of periodontitis. Comprehensive studies have unveiled the double‐edged role of immune response in the development of periodontitis. Immune senescence, which is described as age‐related alterations in immune system, including a diminished immune response to endogenous and exogenous stimuli, a decline in the efficiency of immune protection, and even failure in immunity build‐up after vaccination, leads to the increased susceptibility to infection. Recently, the intimate relationship between immune senescence and periodontitis has come into focus, especially in the aging population. In this review, both periodontal immunity and immune senescence will be fully introduced, especially their roles in the pathology and progression of periodontitis. Furthermore, novel immunotherapies targeting immune senescence are presented to provide potential targets for research and clinical intervention in the future.