title: Innate immune signaling induces interleukin-7 production from salivary gland cells and accelerates the development of primary Sjögren's syndrome in a mouse model.
abstract: Elevated IL-7 in the target tissues is closely associated with multiple autoimmune disorders, including Sjögren'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-γ-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-γ-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-α and IFN-γ 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.
authors.affiliation: Department of Immunology and Infectious Disease, the Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D054370:Chemokine CXCL9; D007370:Interferon Type I; D015851:Interleukin-7; D008024:Ligands; D054367:Receptors, CXCR3; D007371:Interferon-gamma; D011070:Poly I-C