Galectins as novel alarmins in salivary gland inflammation

描述（由申请人提供）：干燥综合征（SS）是一种导致唾液腺破坏的口腔系统自身免疫性疾病。近3%的美国人口受到唾液腺功能减退的影响，这是一种由疾病病因引起的复杂疾病，也是药物治疗的常见副作用。唾液是正常言语、味觉、咀嚼、吞咽和保护口腔软硬组织所必需的重要口腔成分，然而，在SS等疾病中唾液腺被破坏的病因尚不清楚。最近的研究结果提供了强有力的证据，表明像许多炎症性疾病一样，SS起源于对唾液组织的过度活跃的免疫反应并导致腺体破坏。然而，唾液腺中免疫细胞浸润和炎症反应发生的机制仍不清楚。因此，我们的目标是了解导致慢性唾液腺炎症发展的分子事件。新出现的证据表明，在炎症期间，死亡或垂死的宿主细胞可以释放内源性宿主因子，称为警报器。在正常情况下，它们在细胞内具有稳态功能，但一旦在细胞外环境中释放，则表现出趋化和免疫激活特性。目前的证据表明，警报不仅启动，而且扩大和维持正在进行的炎症。这强调了警报因子的识别和表征可以指导针对炎性疾病（如SS）的有效治疗方法的发展。我们正在进行的研究已经确定，半乳糖凝集素-3和-9，宿主c型凝集素，通常在细胞内发现，在细胞外释放，并在细菌感染期间作为警报因子加剧炎症反应。我们的初步研究表明，半乳糖凝集素-3和-9在过表达IL14？(IL14 ?小鼠)表现出SS相关表型（SS小鼠模型）。我们的中心假设是，半乳糖凝集素-3和-9一旦分泌到唾液组织的细胞外环境中，就会通过募集和激活免疫细胞来加剧炎症反应，从而导致SS的发生。为了验证我们的假设，我们将：将半乳糖凝集素-3和-9定性为SS （AIM1）中的新警报因子，并利用半乳糖凝集素-/-或IL14a/半乳糖凝集素-/-小鼠（AIM2）确定半乳糖凝集素-3和-9在唾液腺炎症和变性中的作用。我们期望所提出的实验将为凝血素作为自身免疫性疾病发病机制发展的新警报提供新的见解，包括但不限于SS。

DESCRIPTION (provided by applicant): Sj�gren's syndrome (SS) is an autoimmune disease of the oral system that leads to salivary gland destruction. Almost 3% of the U.S. population is affected by salivary gland hypofunction, a complex disorder resulting from disease etiologies, as well as being a common side effect of drug therapy. Saliva is an essential oral component needed for normal speech, taste, mastication, swallowing, and in protecting the hard and soft tissues of the oral cavity, however the etiology as why salivary glands are destroyed in diseases such as SS is still not known. Recent findings have provided strong evidence that like many inflammatory disorders, SS have its origin in an overactive immune response against salivary tissue and causing glandular destruction. However, the mechanisms underlying infiltration of immune cells and development of inflammatory response in salivary glands remain ill-understood. Thus, our goal is to understand the molecular events that contribute to the development of chronic salivary gland inflammation. Emerging evidence suggests that during inflammation, dead or dying host cells can release endogenous host factors called alarmins. They perform homeostatic functions when contained in intracellular compartments under normal conditions, but exhibit chemotactic and immune activating properties once released in extracellular milieu. Current evidence indicates that alarmins not only initiate but also amplify and sustain on-going inflammation. This underscores that identification and characterization of alarmins can direct the development of effective therapies against inflammatory disorders such as SS. Our ongoing studies have identified that galectin-3 and -9, host C-type lectins, normally found intracellularly, are extracellularly released and act as alarmins to exacerbate inflammatory responses during bacterial infection. Our preliminary studies revealed that both galectin-3 and -9 are abundantly expressed in salivary tissue of transgenic female mice overexpressing IL14? (IL14? mice) exhibiting SS associated phenotypes (mouse model of SS). Our central hypothesis is that galectin-3 and -9, once secreted into the extracellular milieu of salivary tissu, act as alarmins to exacerbate inflammatory responses by recruitment and activation of immune cells resulting in development of SS. To test our hypothesis we will: characterize galactin- 3 and -9 as novel alarmins in SS (AIM1), and determine the role of galectin-3 and -9 in salivary gland inflammation and degeneration using galectin-/- or IL14a/galectin-/- mice (AIM2). We expect that the proposed experiments will provide novel insights into the contribution of galectins as novel alarmins towards the development of pathogenesis of autoimmune diseases, including, but not limited to SS.