β-防御素2在IL-1β介导的活动性牙周炎中的免疫调控功能及其分子机制

The imbalance of host inflammatory/immune response is the main cause of periodontal tissue destruction in the“active period” of periodontitis. The findings from our preliminary work and various researches revealed that IL-1β is the key factor in regulating the inflammatory/immune process of periodontitis, however, the underlying mechanisms were not well understood. Another projects of our group showed a negative correlation between hBD2 and TGF-β, a key regulator of the Th17/Treg balance, moreover, latest research findings also demonstrated that defensins are capable to regulate both the balance of Th17/Treg and IL-1β expression, while IL-17 and IL-22 produced by Th17 cells could enhance inflammation by stimulating the secretion of IL-1β. However, the exact work mechanism of hBD2 in periodontitis progression remains to be elucidated and the links between these factors also needed to be explored. Thus, we hypothesized that “hBD2-TGF-β-Th17/Treg-IL-1β signaling axis would play a dual and important role in the process of periodontitis progression”. In order to verify the hypothesis and explore the mechanism, in vitro and in vivo experimental models of periodontitis progression will be established to investigate how hBD2 regulateTh17/Treg and adjust the expression and function of IL-1β in the “active period” of periodontitis. This comprehensive study will not only provide new insights into mechanisms of periodontitis progression, but also create a new paradigm for the development of new therapeutic approaches in prevention and treatment of periodontitis progression.

免疫炎症调控失衡是活动性牙周炎发生与发展的重要原因。课题组及同行前期证实IL1β是牙周炎进展的关键调节因子，但IL1β在牙周炎进展中的表达调控机制仍不清楚。课题组进一步发现防御素（hBD2）与调控Th17/Treg平衡的关键因子TGFβ呈显著负相关。另外，文献报道hBD2能够参与Th17/Treg平衡及IL1β表达的调控并且Th17可通过IL17/IL21等激活IL1β的表达，但是hBD2在其中具体、准确的免疫学功能与调节机制仍不清楚。因此，我们提出“hBD2可通过TGFβ调节Th17/Treg平衡，进而双重调控IL1β表达，最终实现对牙周炎进展有效调节”的科学假说。为验证该假说，我们将构建牙周炎进展体外、体内研究模型，深入研究分析hBD2如何分化调控Th17/Treg平衡进而调节IL1β表达并最终影响牙周炎进展。研究结果将为牙周炎进展发病机理提供新的科学依据，并为牙周炎防治提供新思路。

牙周炎是一种常见的发生于牙齿支持组织的慢性进行性感染性疾病，是成年人牙齿丧失的首要原因。牙周炎的发展呈“活动期”和“静止期”交替出现，对牙周炎活动期炎症反应及变化的研究有望为控制牙周炎提供新的线索及治疗靶点。本研究就人β防御素（human beta defensins，hBD）调控IL-1β的效果及分子机制进行研究，发现20μg/ml 的HBD2可以上调上调IL-1β，这一作用可能是通过P2X7-K+ efflux-NLRP3-caspase-1信号轴实现的。同时，HBD2处理同时能够再巨噬细胞形成微孔，增加细胞通透性。因此，HBD2在机体免疫炎症反应中发挥重要作用，有望成为一种新的牙周炎防治策略。这一结果尚需在体内研究中得到验证，本研究构建了牙周炎进展模型，发现该方法8-12周可以迅速导致牙槽骨丧失，可以作为牙周炎进展模型使用。同时本项目研究了. IL-22对牙周炎进展的调控作用及分子机制，发现10 ng.ml-浓度的IL-22毒性较小，IL-22对成骨有诱导作用。对破骨的诱导是通过RANKL而非OPG实现，而这一作用是通过p38和erk通路实现的，jnk通路不参与。本项目研究表明HBD2，IL-22在牙周炎进展中发挥重要作用，有望成为新的治疗靶点。