Glycolytic metabolites, Calcium entry and Sjogren’s syndrome

项目摘要 唾液对维持口腔健康至关重要，据估计，在中国有500多万人 美国人患有唾液腺功能障碍。原发性干燥综合征是一种自身免疫性疾病 病因不明和多种因素的疾病被认为在发病机制中起作用。 PSS的一部分。重要的是，渗透免疫细胞(特别是Th17细胞)，产生B细胞的自身抗体，以及 树突状细胞在PSS患者的唾液腺中高度存在；然而，其机制 至于为什么这些免疫细胞存在于唾液组织中，目前尚不清楚。尽管钙离子被证明扮演着一个 在调节唾液分泌以及免疫细胞激活方面的中心作用，关于 PSS中钙离子通道活性的调节机制尚不清楚。内源性代谢物， 例如乳酸，以前被认为是细胞新陈代谢的废物，但最近它 已经证明，这些代谢物有效地调节了免疫反应。L-乳酸抑制T细胞 运动性，从而阻止T细胞从炎症组织中返回，并增加乳酸 在PSS小鼠模型和PSS患者的唾液腺中观察到了这种水平。重要的是，增加 乳酸水平在抑制STIM1迁移从而阻止唾液腺钙离子进入方面起着关键作用 导致内质网钙离子水平下降并诱导内质网应激的细胞。乳酸介导的内质网诱导 应激释放对T/B细胞激活和向唾液组织迁移至关重要的警素。 最后，乳酸介导的Orai1活性丧失导致干扰素和IL-17细胞因子的过度产生。 并抑制线粒体功能，而线粒体功能对代谢重编程很重要 T细胞交换所需的。这笔拨款的目的是为了阐明这一机制(S) 内源性代谢产物，如乳酸，调节钙信号，并导致唾液腺功能障碍。 这一应用是基于乳酸通过抑制钙离子内流而诱导自身免疫的假设。 导致唾液分泌减少和氧化磷酸化抑制的通道。 我们的研究结果有望为内源性代谢物在体内的作用提供新的见解。 唾液腺功能障碍的钙离子通道调控及其分子机制 建立恢复唾液腺功能的方法。对这些事件的更好理解将是 对阐明唾液腺功能障碍的新疗法具有重要意义。

Project Summary Saliva is essential for maintaining oral health and it has been estimated that more than 5 million people in the US suffers from salivary gland dysfunctions. Primary Sjögren's syndrome (pSS) is an autoimmune disease with unknown etiology and multiple factors have been suggested to play a role in the pathogenesis of pSS. Importantly, infiltrating immune cells (especially Th17 cells), autoantibodies producing B cells, and dendritic cells are shown to be highly present in salivary glands of pSS patients; however, the mechanism as why these immune cells are present in salivary tissues is not known. Although Ca2+ is shown to play a central role in regulating saliva secretion as well as in immune cell activation, information regarding the mechanism that modulate Ca2+ channel activity in pSS is not well understood. Endogenous metabolite, such as lactate was previously considered as a waste product of cellular metabolism, but recently it has been shown that these metabolites effectively modulate the immune response. L-lactate inhibit T cell motility thereby preventing the movement of T cells, back from the inflamed tissues and increase in lactate levels are observed in the salivary glands of pSS mouse models and in pSS patients. Importantly, increase in lactate levels were critical in inhibiting STIM1 migration thereby preventing Ca2+ entry in salivary gland cells that lead to a decrease in ER Ca2+ levels and induced ER stress. Lactate-mediated induction of ER stress releases alarmins that is essential for T/B cell activation and their migration into salivary tissues. Finally, lactate-mediated loss of Orai1 activity resulted in the overproduction of IFN and IL-17 cytokines from CD4+ T cells and inhibited mitochondrial function that was important for metabolic reprograming needed for T cell switching. The objective of this grant is to elucidate the mechanism(s) thereby endogenous metabolites, such as lactate modulates Ca2+ signaling and leads to salivary gland dysfunction. This application is based on the hypothesis that lactate induces autoimmunity by inhibiting Ca2+ entry channels which results in decreased saliva secretion and suppression of the oxidative phosphorylation. The results of our studies are expected to provide new insights into the role of endogenous metabolites in regulating Ca2+ channels and the molecular mechanism involved in salivary gland dysfunction as well as establish ways to restore functional salivary glands. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions.