Impaired Differentiation of Langerhans Cells in the Murine Oral Epithelium Adjacent to Titanium Dental Implants

Abstract

Peri-implantitis is a destructive inflammatory process affecting tissues surrounding dental implants and it is considered a new global health concern. Human studies have suggested that the frequencies of Langerhans cells (LCs), the main antigen-presenting cells (APCs) of the oral epithelium, are dysregulated around the implants. Since LCs play a role in regulating oral mucosal homeostasis, we studied the impact of dental titanium implants on LC differentiation using a novel murine model. We demonstrate that whereas the percentage of LC precursors (CD11c+MHCII+) increased in the peri-implant epithelium, the frequencies of LCs (CD11c+MHCII+EpCAM+langerin+) were significantly reduced. Instead, a population of partially developed LCs expressing CD11c+MHCII+EpCAM+ but not langerin evolved in the peri-implant mucosa, which was also accompanied by a considerable leukocyte infiltrate. In line with the increased levels of LC precursors, expression of CCL2 and CCL20, chemokines mediating their translocation to the epithelium, was elevated in the peri-implant epithelium. However, expression of TGF-β1, the major cytokine driving final differentiation of LCs, was reduced in the epithelium. Further analysis revealed that while the expression of the TGF-β1 canonical receptor activing-like kinase (ALK)5 was upregulated, expression of its non-canonical receptor ALK3 was decreased. Since titanium ions releasing from implants were proposed to alter APC function, we next analyzed the impact of such ions on TGF-β1-induced LC differentiation cultures. Concurring with the in vivo studies, the presence of titanium ions resulted in the generation of partially developed LCs that express CD11c+MHCII+EpCAM+ but failed to upregulate langerin expression. Collectively, these findings suggest that titanium dental implants have the capacity to impair the development of oral LCs and might subsequently dysregulate immunity in the peri-implant mucosa.

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

“…One possibility is that monocyte differentiation is an intrinsically inefficient process and may also occur for the generation of tissue-resident macrophages at other sites. Alternatively, monocyte-derived EpCAM + Langerin neg cells can be identified within the oral mucosa, wherein inflammation blocks the transition to mucosal LC (13, 54). Therefore, it is possible that continued inflammation in our model blocks differentiation of EpCAM + cells.…”

Niche Specific Microbiota-Dependent and Independent Bone Loss around Dental Implants and Teeth

“…The model design and surgery protocols used for this study were previously described (Heyman et al 2018). For details, see Appendix.…”

Immunohistochemical assessment of the peri‐implant soft tissue around different abutment materials: A human study

“…Titanium was reported to inhibit T cell activation and inflammatory cytokine release 24 . However, the peri‐implant mucosa was found to be augmented with Tolerogenic regulatory T cells (Tregs), without clinical inflammation, compared with healthy gingiva in a mouse model 25 . In the present study, gold alloy demonstrated higher levels of CD3 + cells when compared with titanium and titanium‐based abutments (Figure 10).…”