TLR7 responses to nucleosides drive sialadenitis in Slc29a3-deficient mice

作者：Takuma Shibata, Kotono Okabe-Kibe, Chen Hu, Kiyoshi Yamaguchi, Daisuke Koga, Masato Taoka, Yuji Motoi, Ryota Sato, Hao-Wen Hsiao, Ryutaro Fukui, Naoki Kaneko, Zhiqin Wang, Yanmei Li, Wei Wei, Zhigang Cai, Yoichi Furukawa, Emi K. Nishimura, Shintaro Kawano, Masafumi Moriyama, Seiji Nakamura, Kensuke Miyake · 发表于：International Immunology · 年份：2025 · DOI：10.1093/intimm/dxaf073 · 被引用次数：2 · 研究领域：Salivary Gland Disorders and Functions、IgG4-Related and Inflammatory Diseases、Liver Diseases and Immunity

Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome. The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradation products such as nucleosides and oligoribonucleotides, the role of these ligands in sialadenitis development remains unclear. Here, we demonstrate that lysosomal accumulation of endogenous nucleosides is sufficient to drive autoimmune sialadenitis. Loss-of-function genetic variations in the nucleoside transporter SLC29A3 cause lysosomal nucleoside accumulation, leading to constitutive activation of TLR7 and TLR8 in monocytes and macrophages. Consequently, macrophages infiltrate multiple organs in mice and humans. In Slc29a3-/- mice, submandibular glands (SMGs) were impaired in saliva production. SLC29A3-deficiency specifically damaged Aqp5+ acinar and intercalated duct cells in SMGs, while sparing neighboring cells such as ductal and myoepithelial cells. Although macrophages accumulated in both the spleen and SMGs, lymphocyte infiltration and production of chemokines, including CXCL9, CXCL13, and CCL5, occurred selectively in SMGs. In IgG4-RD patients, these chemokines were also produced in SMGs, highlighting parallels between sialadenitis in Slc29a3-/- mice and IgG4-RD. These findings indicate that constitutive TLR7 activation by nucleosides is a key mechanism driving autoimmune sialadenitis.