Host defense against oral microbiota by bone-damaging T cells

Abstract

The immune system evolved to efficiently eradicate invading bacteria and terminate inflammation through balancing inflammatory and regulatory T-cell responses. In autoimmune arthritis, pathogenic TH17 cells induce bone destruction and autoimmune inflammation. However, whether a beneficial function of T-cell-induced bone damage exists is unclear. Here, we show that bone-damaging T cells have a critical function in the eradication of bacteria in a mouse model of periodontitis, which is the most common infectious disease. Bacterial invasion leads to the generation of specialized TH17 cells that protect against bacteria by evoking mucosal immune responses as well as inducing bone damage, the latter of which also inhibits infection by removing the tooth. Thus, bone-damaging T cells, which may have developed to stop local infection by inducing tooth loss, function as a double-edged sword by protecting against pathogens while also inducing skeletal tissue degradation.

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

“…To determine the role of SH3BP2 in the pathoetiology of periodontitis, a mouse ligature‐induced periodontitis model was applied to the SH3BP2 knockout mice ( Sh3bp2 −/− ), where an increased oral bacterial load due to accumulation of commensal bacteria within the silk ligature is responsible for periodontal inflammation and subsequent alveolar bone resorption . This ligature model has been widely used to study the molecular mechanisms of periodontitis . To confirm that ligature‐induced periodontitis is dependent on bacterial accumulation surrounding a ligated tooth, we treated a group of 10‐week‐old wild‐type mice with an antibiotic cocktail (ampicillin, vancomycin, kanamycin, metronidazole) in drinking water from 5 days before ligature placement.…”

“…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.…”

“…Osteoclasts are exclusively responsible for alveolar bone resorption in the sequence of events during periodontitis, and receptor activator of nuclear factor‐kappa B ligand (RANKL), which is a member of the TNF cytokine family, is a pivotal cytokine for osteoclastogenesis . Recently, it has been shown that osteoblasts and periodontal ligament cells as well as osteocytes are primary sources of RANKL for osteoclastogenesis in mouse experimental periodontitis models . Notably, IL‐17 produced by T H 17 cells induces RANKL expression by osteoblastic and periodontal ligament cells in a ligature‐induced periodontitis model and stimulates RANKL production by osteocytes in a bone loss model using continuous parathyroid hormone (PTH) treatment …”

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

“…A similar strategy revealed that RANKL produced by osteocytes is critical for inflammatory osteolysis in a periodontitis model (Graves et al., ). Interestingly, RANKL produced by T cells only has a minor role, and that RANKL produced by B cells has even no relevance in this respect (Tsukasaki et al., ). These fundamental discoveries provide insights into how RANKL produced by osteocytes is linked to alveolar bone loss.…”

“…Ligature‐induced periodontitis caused an accumulation of Th17 and neutrophils, while the Tregs were decreased in the oral mucosa. Knockout of IL17A and IL17F inhibited the catabolic changes of periodontitis suggesting a key role of IL17, besides TNFα and IL1, driving inflammatory osteolysis (Tsukasaki et al., ). This is further support for Th17 cells to control the balance between defence and tissue destruction.…”