Innate Immune Signaling Induces Interleukin-7 Production from Salivary Gland Cells and Accelerates the Development of Primary Sjogren's Syndrome in a Mouse Model
Innate Immune Signaling Induces Interleukin-7 Production from Salivary Gland Cells and Accelerates the Development of Primary Sjogren's Syndrome in a Mouse Model
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DOI：
10.1371/journal.pone.0077605
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发表时间：
2013-10-17
期刊：
影响因子：
3.7
通讯作者：
Yu, Qing
中科院分区：
文献类型：
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作者：
Jin, Jun-O;Shinohara, Yoshinori;Yu, Qing
靶组织中IL-7升高与多种自身免疫性疾病密切相关，包括干燥综合征（SS）。我们最近发现IL-7在C57BL/6原发性SS （pSS）的发生和发展中起重要作用。NOD-Aec1Aec2小鼠是一种明确定义的原发性SS小鼠模型。然而，导致过量IL-7产生的环境信号尚未得到很好的表征。先天免疫信号在形成包括自身免疫应答在内的适应性免疫应答中起着至关重要的作用。我们和其他人之前已经证明先天免疫信号可以诱导C57BL/6小鼠肺和肠中IL-7的表达。在这项研究中，我们表征了poly I:C（一种双链RNA类似物和toll样受体3激动剂）对诱导唾液腺中IL-7表达和pSS发展的影响。我们发现，给C57BL/6小鼠注射poly I:C后，以1型IFN-和IFN-依赖性的方式快速诱导唾液腺中IL-7的表达。此外，poly I: c诱导的IL-7有助于唾液腺中CXCL9的最佳上调，这可能随后促进更多ifn - γ生成T细胞的募集。反复给药poly I:C至C57BL/6。NOD-Aec1Aec2小鼠加速了ss样外皮病的发展，这种作用通过中和抗体阻断IL-7受体信号通路而被消除。最后，poly I:C或ifn - α和ifn - γ的组合诱导人唾液腺上皮细胞系中IL-7基因的表达和蛋白的产生。因此，我们证明了IL-7在唾液腺细胞中的表达可以被poly I:C诱导，并描绘了先天免疫信号通过诱导靶组织中的IL-7促进pSS发展的关键机制。
Elevated IL-7 in the target tissues is closely associated with multiple autoimmune disorders, including Sjogren's syndrome (SS). We recently found that IL-7 plays an essential role in the development and onset of primary SS (pSS) in C57BL/6.NOD-Aec1Aec2 mice, a well-defined mouse model of primary SS. However, environmental signals that cause excessive IL-7 production are not well-characterized. Innate immune signaling plays a critical role in shaping the adaptive immune responses including autoimmune responses. We and others have previously shown that innate immune signaling can induce IL-7 expression in lungs and intestines of C57BL/6 mice. In this study, we characterized the effects of poly I:C, a double-stranded RNA analog and toll-like receptor 3 agonist, on the induction of IL-7 expression in salivary glands and on pSS development. We showed that poly I:C administration to C57BL/6 mice rapidly induced IL-7 expression in the salivary glands in a type 1 IFN- and IFN-gamma-dependent manner. Moreover, poly I:C-induced IL-7 contributed to the optimal up-regulation of CXCL9 in the salivary glands, which may subsequently promote recruitment of more IFN-gamma-producing T cells. Repeated administration of poly I:C to C57BL/6.NOD-Aec1Aec2 mice accelerated the development of SS-like exocrinopathy, and this effect was abolished by the blockade of IL-7 receptor signaling with a neutralizing antibody. Finally, poly I:C or a combination of IFN-alpha and IFN-gamma induced IL-7 gene expression and protein production in a human salivary gland epithelial cell line. Hence, we demonstrate that IL-7 expression in the salivary gland cells can be induced by poly I:C and delineate a crucial mechanism by which innate immune signals facilitate the development of pSS, which is through induction of IL-7 in the target tissues.