Galectins as novel alarmins in salivary gland inflammation

描述(申请人提供)：SJ�格林综合征(SS)是口腔系统的一种自身免疫性疾病，会导致唾液腺破坏。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。唾液是正常说话、味觉、咀嚼、吞咽和保护口腔硬组织和软组织所必需的口腔成分，但唾液腺在SS等疾病中被破坏的原因尚不清楚。最近的发现提供了强有力的证据表明，像许多炎症性疾病一样，SS的起源是对唾液组织的过度活跃的免疫反应，并导致腺体破坏。然而，唾液腺中免疫细胞的渗透和炎症反应的发生机制仍不清楚。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，死亡或濒临死亡的宿主细胞可以释放内源性宿主因子，称为警示因子。在正常情况下，当它们被包含在细胞内的隔室中时，它们表现出动态平衡功能，但一旦在细胞外环境中释放，它们就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，而且还放大和维持正在进行的炎症。这强调了对警报的识别和表征可以指导针对SS等炎症性疾病的有效治疗的发展。我们正在进行的研究发现，宿主C型凝集素Galectin-3和-9通常存在于细胞内，在细胞外释放，并在细菌感染过程中作为警报剂加剧炎症反应。我们的初步研究表明，Galectin-3和Galectin-9在高表达IL14？的转基因雌性小鼠唾液组织中大量表达。(IL14？表现出SS相关表型(SS小鼠模型)。我们的中心假设是，Galectin-3和Galectin-9一旦分泌到唾液组织的细胞外环境中，就会作为警报物质，通过招募和激活免疫细胞来加剧炎症反应，从而导致SS的发展。为了验证我们的假设，我们将：在SS(AIM1)中表征Galactin-3和-9作为新的警示蛋白，并使用Galectin-/-或IL14a/Galectin-/-小鼠(AIM2)确定Galectin-3和-9在唾液腺炎症和退化中的作用。我们期望拟议的实验将为Galectins作为新的警报因子在自身免疫性疾病的发病机制中的作用提供新的见解，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.