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。几乎3%的美国人口受到唾液腺功能减退症的影响，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、吞咽和保护口腔硬组织和软组织所需的重要口腔成分，然而，唾液腺在诸如SS的疾病中被破坏的病因学仍然未知。最近的研究结果提供了强有力的证据，像许多炎症性疾病，SS有其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，免疫细胞浸润和炎症反应在唾液腺中的发生机制仍然不清楚。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，在炎症过程中，死亡或垂死的宿主细胞可以释放称为alarmins的内源性宿主因子。它们在正常条件下包含在细胞内隔室中时执行稳态功能，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，alarmins不仅启动，而且放大和维持正在进行的炎症。这强调了alarmins的鉴定和表征可以指导针对炎性疾病如SS的有效疗法的开发。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，是细胞外释放，并作为警报素加剧细菌感染期间的炎症反应。我们的初步研究表明，半乳糖凝集素-3和-9大量表达在唾液组织中的转基因雌性小鼠过表达IL 14？(IL14?小鼠）表现出SS相关表型（SS的小鼠模型）。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，作为警报素，通过募集和激活免疫细胞加剧炎症反应，导致SS的发展。为了检验我们的假设，我们将：将半乳糖凝集素-3和-9表征为SS中的新警报素（AIM 1），并使用半乳糖凝集素-/-或IL 14 α/半乳糖凝集素-/-小鼠（AIM 2）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，所提出的实验将提供新的见解半乳糖凝集素作为新的警报对自身免疫性疾病，包括但不限于SS的发病机制的发展的贡献。

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.