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Trigeminal neurons control immune-bone cell interactions and metabolism in apical periodontitis

ABSTRACT: Apical periodontitis (AP) is an inflammatory disease occurring following tooth infection with distinct osteolytic activity. Despite increasing evidence that sensory neurons participate in regulation of non-neuronal cells, their role in the development of AP is largely unknown. We hypothesized that Nav1.8+ nociceptors regulate bone metabolism changes in response to AP. Methods: A selective ablation of nociceptive neurons in Nav1.8Cre/ DTALox mouse line was used to evaluate the development and progression of AP using murine model of infection-induced AP. Micro-computed tomography examination was applied to quantify osteolytic lesions following induction of AP. Additionally, RT-PCR, RNAscope, and immunohistochemical (IHC) analysis were used to investigate the expression of immune cells, osteoblasts, and osteoclasts. Co-culture of trigeminal ganglia (TG) neurons from DTALox (control) and Nav1.8Cre/ DTALox mice with either IDG-SW3 or MC3T3-E1 osteoblast precursor cell lines or RAW264.7 murine macrophages were used to assess osteoblast and osteoclast function, by RNA sequencing, mineralization, and osteoclastic assays. Results: Ablation of Nav1.8+ nociceptors had earlier progression of AP with larger osteolytic lesions compared to the controls. IHC and RNAscope analysis demonstrated greater number of macrophages, T-cells, osteoclast and osteoblast precursors as well as an increased RANKL:OPG ratio at earlier time points among Nav1.8Cre/ DTALox mice. There was an increased expression of IL-1a and IL-6 within lesions of nociceptor-ablated mice. Further, co-culture experiments demonstrated that TG neurons promoted osteoblast mineralization and inhibited osteoclastic function. Conclusion: The findings suggest that TG Nav1.8+ neurons contribute to modulation of the AP development by delaying the influx of immune cells, promoting osteoblastic differentiation, and decreasing osteoclastic activities. This newly uncovered mechanism could become a therapeutic strategy for the treatment of AP and minimize the persistence of osteolytic lesions in refractory cases.

ORGANISM(S): Mus musculus

PROVIDER: GSE198091 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Apical periodontitis (AP) is a painful inflammatory disease resulting from tooth infection that affects millions worldwide with a marked impact on quality of life and is accompanied by bone loss surrounding the affected tooth. There is growing evidence that the nociceptive fibers densely innervating teeth regulate the disease progression, in addition to their sensorial function. We hypothesized that nociceptors regulate the transcriptomic profile of the periapical osteolytic lesion in a mouse model of AP. Male control (Nav1.8 cre+/-) and nociceptor-ablated (Nav1.8cre+/- DTAlox+/-) mice were generated and underwent pulp exposure procedures on all 4 first molars and at 8 weeks of age. At either 0, 7, or 14 days after pulp exposure, periapical tissues were dissected from mice (n=3-4/strain/time point). Total RNA was extracted from the pooled periapical lesions from each animal and submitted for total RNA sequencing and bioinformatic analysis. We found that pulp exposure triggers the differential expression of hundreds of genes within the periapical lesion over the course of infection with marked differences between in both control and mice with nociception ablation. Importantly, at 14 days post pulp-exposure, 422 genes were differentially expressed between nociceptor-ablated and control mice with greater enrichment of biological processes related to inflammation, specifically immune cell chemotaxis and migration, compared to control mice. Among these inflammatory markers, TNFα, IL-1α, and IL-1β, that are known to play a crucial role in AP were significantly upregulated in nociceptor-ablated mice. In conclusion, nociceptor-ablation regulates the transcriptomic profile of periapical lesions in a mouse model of AP, shifting the gene expression profile to a greater enrichment of inflammatory genes, suggesting nociceptors play a role in the kinetics of the immune response. This newly uncovered neuro-immune axis and its mechanisms in AP can potentially be an important therapeutic target for the treatment of this prevalent disease.

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Trigeminal neurons control immune-bone cell interactions and metabolism in apical periodontitis

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