Inflammatory responses initiated by periodontal bacterial DNA

描述(申请人提供)：宿主免疫系统通过一系列称为模式识别受体(PRRs)的受体来检测病原体相关分子模式(PAMP)，从而对入侵的病原体做出反应。细胞外PRRs及其配体的作用在牙周病的发病机制中具有很好的特征。细菌核酸代表一组主要通过细胞内PRRs识别的PAMP，包括炎症体和DAI的Toll样受体9、AIM2(在黑色素瘤-2中缺失)。最近关于DNA和细胞内DNA受体的贡献的数据已经改变了我们对各种条件下疾病发病机制的看法。这可能适用于牙周感染，事实上，我们实验室进行的研究也支持这一假设。我们的初步研究发现，与健康部位相比，TLR9、AIM2和DAI在牙周病变组织中的表达增加。此外，我们还报道了TLR9启动子中单核苷酸多态(SNP)在牙周病患者和健康受试者中的差异表达。此外，我们还表明，牙周BDNA启动的炎症通路在髓系细胞和非髓系细胞中都是可操作的，这对牙周病理具有重要意义。牙周病不仅局限于牙龈组织，还与各种系统性疾病有关。对远距离牙周BDNA的鉴定表明，BDNA启动的炎症途径可能不仅在牙周病理中起重要作用，而且还可能导致牙周病对全身健康的不利影响。因此，确定牙周BDNA启动的信号通路的生物学机制以及它们与其他PAMP和PRRs的相互作用对于了解它们在牙周炎和系统性疾病发病机制中的重要性是非常重要的。我们认为，DNA在组织中的累积效应可能直接促进了高炎症状态和/或干扰了其他PAMP和改变免疫反应的信号通路。这项建议旨在将我们先前的研究扩展到人和小鼠的原代巨噬细胞，以确定牙周BDNA及其受体在细胞因子诱导、耐受/交叉和协同作用中的作用。

DESCRIPTION (provided by applicant): The host immune system responds to invading pathogens by detecting pathogen-associated molecular patterns (PAMPs) through an array of receptors called pattern recognition receptors (PRRs). The role of extracellular PRRs and their ligands are very well characterized in the pathogenesis of periodontal disease. Bacterial nucleic acids represent a group of PAMPs that are mainly recognized through intracellular PRRs, including Toll like receptor 9, AIM2 (absent in melanoma-2) for inflammasome and DAI. Recent data regarding the contribution of DNA and intracellular DNA receptors has changed our view of disease pathogenesis in a variety of conditions. This may be true for periodontal infections and in fact, studies conducted in our laboratory also support this hypothesis. Our preliminary studies identified increased expression of TLR9, AIM2 and DAI in periodontally diseased tissues compared to healthy sites. Furthermore, we also reported differential expression of a single nucleotide polymorphism (SNP) in the TLR9 promoter in periodontally-diseased versus -healthy subjects. Moreover, we also showed that periodontal bDNA-initiated inflammatory pathways are operant both in myeloid and non-myeloid cells of importance for periodontal pathology. Periodontal disease is not only limited to gingival tissues but also is associated with various systemic diseases. Identification of periodontal bDNA in distant sites suggests that bDNA-initiated inflammatory pathways may not be only important in periodontal pathology but also contribute to periodontal disease adverse effects on systemic health. Hence, it is important to determine the biological mechanisms involved in periodontal bDNA-initiated signaling pathways and their interactions with other PAMPs and PRRs to understand their importance in the pathogenesis of periodontitis and systemic diseases. We believe, cumulative effect of DNA in the tissues may either directly promotes a hyper-inflammatory state and/or interferes with other PAMPs and signaling pathways modifying the immune responses. This proposal is designed to extend our previous studies to primary human and mouse macrophages determine the role of periodontal bDNA and its receptors with regard to induction of cytokines, tolerance/cross and synergy.