TRAF3IP2–IL-17 Axis Strengthens the Gingival Defense against Pathogens
Year: 2022
Type: article
Abstract: Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor–associated factor 3 interacting protein 2 ( TRAF3IP2), a gene encoding the gate-keeping interleukin (IL)–17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the TRAF3IP2 locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17–mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. Traf3ip2 null mice ( Traf3ip2 –/– ) were more susceptible than wild-type (WT) mice to the Porphyromonas gingivalis–induced periodontal alveolar bone loss. Such bone loss was associated with a delayed P. gingivalis clearance and an attenuated neutrophil recruitment in the gingiva of Traf3ip2 –/– mice. Transcriptomic data showed decreased expression of antimicrobial genes, including Lcn2, S100a8, and Defb1, in the Traf3ip2 –/– mouse gingiva in comparison to WT mice prior to or upon P. gingivalis oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the Traf3ip2 –/– mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of Streptococcus genus bacteria. More P. gingivalis was observed in the Traf3ip2 –/– mouse gingiva than WT control animals in a ligature-promoted P. gingivalis invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by P. gingivalis. Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.
Source: Journal of Dental Research
Language: English
Subfield: Periodontics
Field: Dentistry
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Awards: G1135917780, G1243299691, G1527150935, G1691174148, G173303992, G1941623656, IFI16 is a Periodontitis Modulating Protein, G2818629771, G3114902838, G3410686264, G3462919067, GWA for Gene-Environment Interaction Effects Influencing CHD, G457330776, Investigating the role of Tumor Necrosis Factor-Receptor Associated Factor 3 Interacting Protein 2 , Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G567847597, Robust immunoprevention strategies for high-risk oral epithelial dysplasia, G6548750934, GENOME-WIDE ASSOCIATION STUDY OF PERIODONTAL DISEASE, The Rolde of IL-37b from Plasma Cells in Periodontitis Pathogenesis, Restoring the Immunogenicity of Head and Neck Cancer, Center for Gastrointestinal Biology and Disease, New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer, UNC Center for Environmental Health and Susceptibility, Nutrition Obesity Research Center (NORC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, SYSTEMIC EFFECTS OF PERIODONTITIS
OpenAlex ID: W4307229611