TRAF3IP2–IL-17 Axis Strengthens the Gingival Defense against Pathogens

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.

Casp11 Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis

“…In periodontal disease, studies observed that Casp11 deficiency led to an elevated bacterial load of P.g or F. nucleatum in gingival tissue (Almeida-da-Silva et al 2019; De Andrade et al 2021). Another study also reported alterations in microbiota due to deletion of an inflammation-related gene Traf3ip2 in PD (Zhang, Sun, et al 2023). In favor of previous reports, our study revealed alterations in the composition of the subgingival microbiota with Casp11 -/- mice compared with WT mice.…”

“…For example, it has been found that recruitment of leukocytes was involved, in which Caspase-11 influences the abundance of P.g (Almeida-da-Silva et al 2019). The IL-17–TRAF3IP2 pathway was also found to be a regulator of oral plaque composition, subsequently influencing alveolar bone loss (Zhang, Sun, et al 2023).…”

IL-17: Balancing Protective Immunity and Pathogenesis

“…Periodontitis is a common chronic inflammatory disease caused by microbial infection in the susceptible hosts and it has been documented that IL-17 plays both protective and destructive roles in the progression of periodontitis [ 37 , 38 ]. Some studies have found that IL-17 dominated the inflammatory network associated with periodontitis traits [ 39 , 40 ] ( Table 1 ), which indicated that abnormal inflammatory responses induced by IL-17 may cause tissue damage. One potential mechanism is that IL-17 is able to amplify inflammation through excessive neutrophil recruitment by enhancing proinflammatory cytokine/chemokine production, which results in further osteoclast activation and bone resorption [ 41 ].…”

“…Homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen. [39,40] Encephalomyelitis IL-17-mediated positive feedback loop of IL-6 signaling through NF-κB and STAT3 contributes to enhanced autoimmune encephalomyelitis. [47] Virus associated inflammation Bone marrow-derived IL-17A is required for the development of pneumonitis.…”