Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Program in Neuroscience, Center to Advance Chronic Pain Research, Baltimore, MD, USA.
Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry, Baltimore, MD, USA.
J Dent Res. 2022 Jul;101(7):812-820. doi: 10.1177/00220345211069956. Epub 2022 Jan 27.
Periodontitis is a highly prevalent chronic inflammatory disease that progressively destroys the structures supporting teeth, leading to tooth loss. Periodontal tissue is innervated by abundant pain-sensing primary afferents expressing neuropeptides and transient receptor potential vanilloid 1 (TRPV1). However, the roles of nociceptive nerves in periodontitis and bone destruction are controversial. The placement of ligature around the maxillary second molar or the oral inoculation of pathogenic bacteria induced alveolar bone destruction in mice. Chemical ablation of nociceptive neurons in the trigeminal ganglia achieved by intraganglionic injection of resiniferatoxin decreased bone loss in mouse models of experimental periodontitis. Consistently, ablation of nociceptive neurons decreased the number of osteoclasts in alveolar bone under periodontitis. The roles of nociceptors were also determined by the functional inhibition of TRPV1-expressing trigeminal afferents using an inhibitory designer receptor exclusively activated by designer drugs (DREADD) receptor. Noninvasive chemogenetic functional silencing of TRPV1-expressing trigeminal afferents not only decreased induction but also reduced the progression of bone loss in periodontitis. The infiltration of leukocytes and neutrophils to the periodontium increased at the site of ligature, which was accompanied by increased amount of proinflammatory cytokines, such as receptor activator of nuclear factor κΒ ligand, tumor necrosis factor, and interleukin 1β. The extents of increase in immune cell infiltration and cytokines were significantly lower in mice with nociceptor ablation. In contrast, the ablation of nociceptors did not alter the periodontal microbiome under the conditions of control and periodontitis. Altogether, these results indicate that TRPV1-expressing afferents increase bone destruction in periodontitis by promoting hyperactive host responses in the periodontium. We suggest that specific targeting of neuroimmune and neuroskeletal regulation can offer promising therapeutic targets for periodontitis supplementing conventional treatments.
牙周炎是一种高发的慢性炎症性疾病，它会逐渐破坏牙齿支撑结构，导致牙齿脱落。牙周组织由丰富的表达神经肽和瞬时受体电位香草素 1（TRPV1）的疼痛感受初级传入纤维支配。然而，伤害性神经在牙周炎和骨破坏中的作用仍存在争议。结扎上颌第二磨牙或口腔接种致病菌可诱导小鼠牙槽骨破坏。通过三叉神经节内注射树脂毒素化学消融伤害性神经元可减少实验性牙周炎小鼠的骨丢失。同样，在牙周炎下，伤害性神经元的消融减少了牙槽骨中破骨细胞的数量。伤害感受器的作用也可以通过使用抑制性 Designer 药物（DREADD）受体对表达 TRPV1 的三叉神经传入纤维的功能抑制来确定。非侵入性化学遗传功能性沉默表达 TRPV1 的三叉神经传入纤维不仅减少了诱导，而且还减轻了牙周炎中骨丢失的进展。白细胞和中性粒细胞向牙周组织的浸润在结扎部位增加，伴随着促炎细胞因子如核因子 κΒ 配体受体激活剂、肿瘤坏死因子和白细胞介素 1β的增加。在伤害感受器消融的小鼠中，免疫细胞浸润和细胞因子增加的程度明显降低。相比之下，在对照和牙周炎条件下，伤害感受器的消融并没有改变牙周微生物组。总之，这些结果表明，表达 TRPV1 的传入纤维通过促进牙周组织中过度活跃的宿主反应来增加牙周炎中的骨破坏。我们建议，针对神经免疫和神经骨骼调节的特定靶向治疗可能为牙周炎提供有前途的治疗靶点，补充传统治疗方法。
