Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss

Abstract

Periodontitis is one of the most prevalent human inflammatory diseases. It is characterized by periodontal tissue destruction, progressively driven by the host response. In this regard, cytokines associated with tissue destruction, such as interleukin (IL)–6 and IL-23, use a common signaling pathway mediated by STAT3. This transcription factor is also needed for IL-17A production, a key mediator in periodontitis pathogenesis. Although several studies have reported increased activation of STAT3 in experimental periodontitis, a detailed characterization of STAT3 activation in human gingival tissues and its involvement in alveolar bone loss has yet to be explored. Using a cross-sectional study design, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health, particularly in epithelial cells and T cells. Other cell types of hematopoietic and nonhematopoietic origin also display STAT3 activation in gingival tissues. We detected increased STAT3 phosphorylation and expression of STAT3-related genes during experimental periodontitis. Next, we evaluated the role of STAT3 in alveolar bone destruction using a mouse model of STAT3 loss of function (mut-Stat3 mice). Compared with controls, mut-Stat3 mice had reduced alveolar bone loss following ligature-induced periodontitis. We also evaluated pharmacologic inhibition of STAT3 in ligature-induced periodontitis. Like mut-Stat3 mice, mice treated with STAT3 small-molecule inhibitor had reduced bone loss compared with controls. Our results demonstrate that STAT3 activation is increased in epithelial and T cells during periodontitis and indicate a pathogenic role of STAT3 in inflammatory alveolar bone loss.

Keywords

gingiva periodontal diseases signal transduction inflammation mouth mucosa mucosal immunity

Introduction

Periodontitis is an inflammatory, multifactorial pathology associated with a dysbiotic microbiome characterized by the progressive destruction of periodontal tissues (Papapanou et al. 2018). Severe forms of this disease affect about 796 million people worldwide and are a significant cause of tooth loss, reducing quality of life and posing a significant public health problem and socioeconomic burden (Bernabe et al. 2020). Severe periodontitis adversely affects systemic health, and its treatment improves markers of systemic diseases (Hajishengallis and Chavakis 2021). The standard therapeutic approach does not resolve all clinical cases of periodontitis (Leow et al. 2022). Therefore, it is vital to have a detailed insight and understanding of periodontitis pathogenesis, which could allow the development of new strategies to prevent and limit tissue damage in this disease.

Changes in subgingival microbial communities activate pathways that increase the secretion of cytokines, which are critical in orchestrating periodontal homeostasis and tissue destruction (Hajishengallis 2014). Some of these cytokines, such as the interleukin (IL)-6 family of cytokines, IL-10, IL-20, IL-21, IL-22, and IL-23, use a common intracellular signaling pathway mediated by signal transducer and activator of transcription 3 (STAT3; Hillmer et al. 2016). It is well documented that STAT3 tightly regulates T helper (Th)17 differentiation and IL-17A expression (Durant et al. 2010), both critical for tissue destruction in periodontitis (Dutzan et al. 2018). STAT3 also regulates the expression of IL-17F, the transcription factor RORγt, and the suppressor of cytokine signaling 3 (SOCS3; Durant et al. 2010; Hillmer et al. 2016). In the STAT3 signaling pathway, cytokines such as IL-6 bind to Janus kinases-associated receptors, which will phosphorylate STAT3 on Tyr705 (pSTAT3). Activated STAT3 dimerizes and translocates to the nucleus inducing gene expression (Levy and Lee 2002). Nonphosphorylated STAT3 is increased during periodontitis (Ambili et al. 2017). Animal models have demonstrated increased STAT3 phosphorylation during periodontal tissue destruction and the feasibility of inhibiting STAT3 to restrain alveolar bone loss (Chaves de Souza et al. 2013; Hu et al. 2021; Zhang et al. 2021). However, a detailed characterization of STAT3 activation in human gingival tissues and the effects of STAT3 loss of function in the immunopathology of periodontitis has yet to be explored.

This present study detected increased proportions and numbers of pSTAT3-positive cells in human gingival tissues during periodontitis compared with health, particularly in epithelial and T cells. We also detected increased pSTAT3 and STAT3-related gene expression during experimental periodontitis. Notably, STAT3 loss of function and STAT3 small-molecule inhibition reduced alveolar bone loss in ligature-induced periodontitis. Our results indicate a detrimental role of STAT3 in periodontal tissue destruction.

Materials and Methods

Subjects

All subjects signed informed consent and enrolled in an ethics committee-approved protocol (NCT05506098) at the University of Chile, Faculty of Dentistry, Dental Clinic from 2019 to 2022. Inclusion and exclusion criteria are listed in the Appendix. This study complies with the STROBE checklist of cross-sectional studies. The description of the gingival biopsies and tissue processing together with the immunofluorescence methods are described in the Appendix section.

Mouse Strains

C57BL/6N mice were bred and maintained under specific pathogen-free (SPF) conditions at the University of Chile, Faculty of Dentistry. Mut-Stat3 mice (C57BL/6 genetic background; Steward-Tharp et al. 2014) were kindly provided by Dr. J. O’Shea (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health) and bred and maintained under SPF conditions at the National Institute of Dental and Craniofacial Research veterinary resources core animal facilities. All experiments were approved by appropriate governing bodies and performed following local rules. This study complies with the ARRIVE guidelines.

STAT3 Inhibition

C188-9 (Millipore Sigma) or vehicle (DMSO, Sigma-Aldrich) was injected intraperitoneally at the concentration previously described (50 mg/kg per day; Hox et al. 2016). Injections started 7 d before induction of experimental periodontitis and were given until the day of euthanasia, as previously described (Dutzan et al. 2018).

The methodology for the experimental periodontitis, immunohistochemistry, protein immunoblots, and gene expression assays are detailed in the Appendix.

Statistics

Data analyses were performed using Prism version 9.4.1 (GraphPad Software). Data distribution was evaluated with the Shapiro-Wilk test. Differences were assessed with the tests described in the figure legends. P values less than 0.05 were considered to be statistically significant.

Results

Increased STAT3 Phosphorylation in Human Gingival Tissues with Periodontitis

First, we queried the presence and distribution of pSTAT3 in human gingival tissues. We observed pSTAT3 during health and periodontitis in gingival tissues. Compared with health, the proportion of pSTAT3-positive cells increased in gingival tissues during periodontitis (28.9% vs. 41.9% P = 0.0055; Fig. 1A–C). This increase in pSTAT3 was observed in the gingival tissue epithelium and lamina propria. In clinically healthy gingiva, 32% of the cells at the epithelial compartment were positive for pSTAT3 versus 49% of cells during periodontitis (a 0.5-fold increase, P = 0.0003). On the other hand, the proportion of pSTAT3-positive cells in the lamina propria increased from 26% in health to 37% during disease (0.4 fold, P = 0.0239; Fig. 1G).

Due to the capacity of different cell subtypes to activate STAT3, we then characterized the pSTAT3-positive cells in gingival tissues in health and periodontitis. We detected that these cells were of hematopoietic (CD45⁺) and nonhematopoietic (CD45⁻) origin. During periodontitis, we observed an increase in the proportion of pSTAT3 cells that were CD45⁺ (19% vs. 32.98%, P = 0.0098) compared with healthy gingival tissues (Fig. 1D–F). More specifically, T cells (CD3⁺), B cells (CD20⁺), macrophages (CD68⁺), and neutrophils (MPO⁺) were the cell subpopulations positive for pSTAT3 in health and diseased gingival tissues (Fig. 2A–L and Appendix Figs. 1 and 2). On the other hand, in the nonhematopoietic compartment, we observed that epithelial cells (cytokeratin-5⁺), endothelial cells (CD31⁺), and fibroblasts (vimentin⁺) were positive for pSTAT3 in gingival tissues (Fig. 3A–I and Appendix Figs. 1 and 2). We detected higher proportions of pSTAT3-positive T cells (11.64% vs. 27.28%, P = 0.0159) and epithelial cells (17.15% vs. 42.35%, P = 0.0126). The total number of pSTAT3-positive cell subpopulation are shown in Appendix Figure 2. We observed increased numbers of positive T cells, neutrophils, and epithelial cells for pSTAT3.

STAT3-Related Gene Expression in Human Epithelial Gingival Cells

The role of STAT3 in T cells during periodontitis has been previously explored by our group (Dutzan et al. 2018). The absence of STAT3 in CD4⁺ T cells diminished bone loss in the ligature-induced periodontitis model. To gain insight into the possible role of STAT3 activation on gingival epithelial cells during periodontitis, we reanalyzed the scRNAseq data from the human oral mucosa cell atlas (Williams et al. 2021). We focused on STAT3-related gene expression in gingival epithelial cells during health and periodontitis (Fig. 3J). Our reanalysis showed that during periodontitis, the expression of most STAT3 activators and target genes analyzed increased. The functions of these genes are related to immune response, cell proliferation, antiapoptosis, tissue destruction, danger signals, angiogenesis, chemokines, and microbial recognition. Genes related to neutrophil chemoattraction, such as CXCL1 and CXCL8, increased their average expression and the percentage of gingival epithelial cells that expressed those genes during periodontitis, suggesting a possible role of STAT3 in neutrophils recruitment by epithelial cells during periodontitis.

Increased STAT3 Phosphorylation in Experimental Periodontitis

To study the role of pSTAT3 in periodontitis through cause-and-effect experiments in mice, we first evaluated the activation of STAT3 in mouse gingival tissues during health and the ligature-induced periodontitis model (LIP; Fig. 4A–C). Similar to human gingival tissues, we detected pSTAT3 in mouse gingiva during health and disease. We observed increased pSTAT3 in ligated gingival tissues compared with control (Fig. 4G–H). In healthy gingival tissues, pSTAT3 was located in well-defined areas of the epithelia and lamina propria, particularly in the basal layer’s cells and in cells of the lamina propria located close to the epithelia and blood vessels. During experimental periodontitis, the number of positive cells for pSTAT3 increased (151 vs. 833, P = 0.0080; Fig. 4D–F), occupying a wider area of the epithelia and the connective tissue between molars. Our flow cytometry analysis revealed a trend of increased proportions (P = 0.0556) and numbers (P = 0.0981) of pSTAT3-positive cells in the hematopoietic compared with the nonhematopoietic compartments during LIP (Appendix Fig. 3).

We also evaluated the gene expression of a group of genes associated with STAT3 in gingival tissues. All assessed genes were expressed in gingival tissues during health and experimental periodontitis. During LIP, the expression of Il6, Il10, Il11, Il23a, and Osm (which encode for cytokines that activate STAT3) was increased compared with control tissues. In addition, genes whose transcription is promoted by STAT3, such as Il17a, Il17f, Il23a, Rorc, Socs3, and Stat3, were also overexpressed in experimental periodontitis. These results suggest an involvement of STAT3 in the regulation of tissue destruction, which characterizes periodontitis (Fig. 4I).

STAT3 Is Causally Involved in Periodontal Bone Destruction

To evaluate the contribution of STAT3 in alveolar bone destruction in periodontitis, we performed the LIP model in mice with a mutation in the Stat3 gene (Steward-Tharp et al. 2014). Mice that express this mutation have a reduction of STAT3 signaling, which phenocopy patients with hyperimmunoglobulin E syndrome (HIES) characterized by STAT3 loss of function in hematopoietic and stromal cells. At steady state, both mut-Stat3 and their littermates showed similar histological characteristics with no sign of inflammation or tissue destruction (Appendix Fig. 4). First, we determined the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) in 6 previously described sites (Fig. 4A–C; Abe and Hajishengallis 2013). We observed higher CEJ-ABC distance in ligated molars than in control (nonligated) molars (Fig. 5A). When we compared this distance between ligated sites, mut-Stat3 mice had diminished CEJ-ABC distance compared with littermate control mice (Fig. 5A). We also analyzed the total bone loss on the ligated side relative to the contralateral nonligated (control) side for each mouse. Wild-type littermate mice had increased bone loss compared with mut-Stat3 mice (Fig. 5B). These results indicate that STAT3 loss of function in hematopoietic and stromal cells protects from inflammatory bone loss in LIP.

To evaluate the STAT3-related immune response in mut-Stat3 mice after LIP, we determined the total numbers of CD45⁺ cells, neutrophils, Th17 cells, and the expression of inflammatory genes. We observe similar numbers of CD45⁺ cells and neutrophils (Appendix Fig. 5A–D) in mut-Stat3 and their littermates during LIP. Importantly, we did not find a statistical difference when comparing the Th17 cell numbers in mut-Stat3 between control and ligated sites (Appendix Fig. 5E and F). Analyzing the gene expression of inflammatory cytokines, we observe similar findings. All genes increased their expression after LIP in mut-Stat3 mice. However, the only gene that did not reach statistical difference was Il17a (Appendix Fig. 6A–H).

To strengthen this finding through an independent (pharmacologic) approach, we also determined whether small-molecule inhibition of STAT3 could reduce ligature-induced bone loss. To this end, we treated wild-type mice with C188-9, an inhibitor with a proven capacity to inhibit STAT3 in different inflammatory mice models (Gavino et al. 2016; Hox et al. 2016; Zhang et al. 2021). Similar to mut-Stat3 mice, ligated C188-9–treated mice showed a diminished CEJ-ABC distance and bone loss compared with vehicle-treated mice (Fig. 5C and D). Therefore, our study shows that a small-molecule inhibitor of STAT3 can protect against inflammatory bone loss in experimental periodontitis.

Discussion

STAT3 transmits signals from the cellular membrane to the nucleus from diverse cytokine families (Hillmer et al. 2016). Many of these cytokines have been associated with clinical signs, inflammation, and alveolar bone destruction in periodontitis (Garlet 2010). In the present work, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health. This increment is explained by a growth in the proportions and numbers of pSTAT3-positive cells from the basal epithelial layer and hematopoietic cells, particularly T cells. To comprehend the function of STAT3 activation in periodontitis pathogenesis, we used a mouse model of LIP. Similar to humans, we detected increased levels of pSTAT3 and increased expression of STAT3-activating cytokines and STAT3 target genes in gingival tissues during experimental periodontitis compared with control. Using mice with STAT3 loss of function, we evaluated the involvement of this transcription factor in the inflammatory alveolar bone destruction associated with periodontitis. We found that mice with STAT3 loss of function had diminished alveolar bone loss and accumulation of Th17 cells compared with wild-type mice during LIP. Consistently, small-molecule STAT3 inhibition protected mice from LIP alveolar bone loss, indicating a role of STAT3 in inducing periodontitis immunopathology.

Our study demonstrated that STAT3 is activated in clinically healthy human gingival tissues and nonligated murine gingival tissues, particularly in the basal layer of the epithelium. STAT3 is critical for skin and mucosa epithelium homeostasis and pathology. It induces keratinocyte differentiation and participates in cell proliferation, survival, and migration. Keratinocyte-specific ablation of Stat3 leads to impaired skin remodeling and wound healing (Sano et al. 1999). In addition, mice with a specific deletion of Stat3 in intestinal epithelial cells are highly susceptible to experimental colitis (Pickert et al. 2009). In the oral mucosa, STAT3 activation has been associated with wound-healing processes and immunity to Candida albicans, underscoring its importance in the oral epithelium homeostasis (Yu et al. 2016; Aggor et al. 2020). In addition, 75% of AD-HIES individuals manifest oral mucosal lesions in the palate and tongue, and 86% present with recurrent oral fungal infections (Freeman et al. 2009; Abusleme et al. 2018), indicating an epithelial barrier dysfunction at the oral mucosa in subjects with STAT3 loss of function. Based on the literature and our results, we speculate that STAT3 plays a homeostatic role in gingival epithelial cells. However, studies in relevant animal models are needed to dissect the physiological role of STAT3 at the gingival epithelium.

Our analysis indicates a trend of increased STAT3 phosphorylation in the human gingival epithelium compared with lamina propria during disease. Similar to what is observed in the epidermal keratinocytes during psoriasis (Sano et al. 2005), we detected increased phosphorylation of STAT3 in gingival keratinocytes during periodontitis. These data were confirmed by our sc-RNA seq analysis of the human oral cell atlas. This increase in STAT3 activation could be related to the augmented levels of IL-6 during periodontitis (Stadler et al. 2016) induced by the elevated Toll-like receptor expression and signaling in crosstalk with complement activation in response to the bacterial dysbiosis observed in periodontitis (Hajishengallis et al. 2004; Abusleme et al. 2021; Wang et al. 2022). Indeed, our study demonstrates an increased expression of Il6 and other cytokines, which signal through the STAT3 pathway during ligature-induced periodontitis.

IL-6 is critical to homeostatic Th17 cell accumulation in gingival tissues and, together with IL-23, is key to pathological Th17 cell proliferation in gingival tissues during periodontitis (Dutzan et al. 2017, 2018). Th17 cells are essential drivers of immunopathology in periodontitis (Dutzan et al. 2018), and STAT3 is critical for their development and pathogenicity (Yang et al. 2007; Durant et al. 2010). In the present study, we detected that mice with STAT3 loss of function and mice treated with STAT3 inhibitor were protected from LIP alveolar bone loss. Previous studies have shown that mut-Stat3 mice lack circulating Th17 cells (Steward-Tharp et al. 2014) and that STAT3 inhibition with C188-9 diminished local and systemic Th17 cells (Gavino et al. 2016; Zhang et al. 2021). Our group also demonstrated that STAT3 expression on CD4⁺ T cells is essential for Th17 cell accumulation and alveolar bone loss in experimental periodontitis. In the same study, we demonstrated that AD-HIES individuals lack Th17 cells in gingival tissues and also present with diminished gingival inflammation and clinical attachment loss compared with a healthy individual cohort (Dutzan et al. 2018). We detected an increase in Th17 cells and Il17a expression after LIP. However, the magnitude of this increase was less in mut-Stat3 compared to littermate controls. Therefore, it is plausible to hypothesize that the loss of function or inhibition of STAT3 diminishes ligature-induced periodontitis bone loss due to reduced numbers or pathogenicity of Th17 cells.

Our results showed that B cells, macrophages, and neutrophils colocalized with pSTAT3 in gingival tissues during periodontitis, the latter with increased numbers but not proportions in diseased gingival tissues. STAT3 transduces signals from cytokines that generate plasma and memory B cells, including IL-21, IL-27, and IL-6. AD-HIES patients lack memory B cells and, like mut-Stat3 and Cd19^cre Stat3^f/f mice, have defects in IgG antigen-specific responses. Defective T follicular helper (Tfh) cell generation may further compromise this humoral response, as Tfh differentiation requires STAT3 (Kane et al. 2014; Steward-Tharp et al. 2014; Hillmer et al. 2016). In phagocytes, including neutrophils and macrophages, STAT3 has an anti-inflammatory role, suppressing signal transduction induced by toll-like receptors and mediating the signals of IL-10. On the other hand, STAT3 regulates critical steps during granulopoiesis and neutrophil migratory response by transducing the granulocyte colony-stimulating factor signal and modulation of neutrophil chemoattractant receptor CXCR2 signal transduction (Nguyen-Jackson et al. 2010). Studies performed in mice with specific deletion of Stat3 in B cells, macrophages, and neutrophils are required to dissect the function of STAT3 in those cell subtypes in gingival tissues during health and periodontitis.

We demonstrated that STAT3 is also activated in non–immune cell constituents of the gingival lamina propria. CD31 and vimentin-positive cells also colocalized with pSTAT3 in the lamina propria of the gingiva. In endothelial cells, STAT3 regulates vascular barrier integrity and is activated through cytokines receptors such as GP130 and VEGFR-2 (Yun et al. 2017; Wang et al. 2021). In fibroblasts, STAT3 is a central integrator of multiple profibrotic signals participating in the fibroblasts to myofibroblasts transition and collagen release (Chakraborty et al. 2017).

One of the limitations of our study is that healthy individuals were significantly younger than those in the periodontitis group, which might have affected our results. Animal studies demonstrated a significantly downregulated pSTAT3 in old mice and senile rats compared with younger mice (Mohamed and Sayed 2020; Chang et al. 2022) and significantly less circulating STAT3 expression in older rats (Chang et al. 2022).

On the other hand, our animal experiments were not performed in sex-matched cohorts. Evidence demonstrates that females appear more susceptible to periodontal bone loss than male mice do (Duan et al. 2016). However, in our experiments, we included littermates and animals of both sexes.

In a clinical situation, periodontitis is detected once it is established. Therefore, and to increase the translatability of our work, our next step will be to evaluate whether C188-9 or other inhibitors could restrain tissue destruction after disease establishment.

Despite the limitations, our findings demonstrate that STAT3 phosphorylation increases during periodontitis, specifically in T and epithelial cells, and its loss of function and inhibition diminishes alveolar bone loss. These results indicate a possible role of STAT3 in inflammatory alveolar bone destruction and place this transcription factor as a potential therapeutic target for periodontitis.

Conclusions

STAT3 is activated in gingival tissues in homeostatic conditions and increases its phosphorylation during periodontitis. This expansion of pSTAT3-positive cells is principally due to increased proportions of epithelial and T cells that phosphorylate STAT3 during periodontitis compared with health. Our work also demonstrated that the loss of function of STAT3 or its pharmacologic inhibition restrains bone loss in an animal model of periodontal tissue destruction, indicating that STAT3 might play a role in inflammatory tissue destruction during periodontitis.

Author Contributions

M. Arce, contributed to the data acquisition, analysis, and interpretation, drafted the manuscript; M. Rodriguez-Peña, contributed to the data acquisition, analysis, and interpretation, critically revised the manuscript; J. Espinoza-Arrue, R.A. Godoy, M. Reyes, T. Greenwell-Wild, contributed to the data acquisition and analysis, critically revised the manuscript; T. Kajikawa, contributed to data acquisition, analysis and interpretation of the data, critically revised the manuscript; G. Hajishengallis, contributed to data interpretation of the data, critically revised the manuscript; L. Abusleme, contributed to conception and design, data acquisition, analysis and interpretation of the data, critically revised the manuscript; N. Moutsopoulos, contributed to conception and design, data interpretation of the data, critically revised the manuscript; N. Dutzan, contributed to conception and design, data acquisition, analysis and interpretation of the data, drafted the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Supplemental Material

sj-docx-1-jdr-10.1177_00220345231192381 – Supplemental material for Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss

Supplemental material, sj-docx-1-jdr-10.1177_00220345231192381 for Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss by M. Arce, M. Rodriguez-Peña, J. Espinoza-Arrue, R.A. Godoy, M. Reyes, T. Kajikawa, T. Greenwell-Wild, G. Hajishengallis, L. Abusleme, N. Moutsopoulos and N. Dutzan in Journal of Dental Research

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by projects FONDECYT 11180389, FONDECYT 1231350 (N. Dutzan), FONDECYT 11180505, FONDECYT 1231728 (L. Abusleme), the Intramural Program of the National Institute of Dental and Craniofacial Research (N. Moutsopoulos), DE029436 (G. Hajishengallis). M. Arce is a recipient of scholarship ANID 21221003 from the Chilean Government. We thank the Dental Clinic and Experimental Platform from the Faculty of Dentistry, University of Chile. We thank the NIDCR Veterinary Resource Core. We thank Lorena Labra for their technical expertise.

ORCID iDs

M. Arce

G. Hajishengallis

L. Abusleme

N. Dutzan

A supplemental appendix to this article is available online.

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