TLR7 responses to nucleosides drive sialadenitis in Slc29a3-deficient mice

Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome (SS). 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.

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Journal
International Immunology
Published
2025-12-02
DOI
https://doi.org/10.1093/intimm/dxaf073
Primary Topic
Salivary Gland Disorders and Functions
Type
article
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article

TLR7 responses to nucleosides drive sialadenitis in Slc29a3-deficient mice

Yuji Motoi, Kiyoshi Yamaguchi, Emi K. Nishimura, Yoichi Furukawa et al.
International Immunology
Salivary Gland Disorders and Functions
article

TLR7 responses to nucleosides drive sialadenitis in Slc29a3-deficient mice

Yuji Motoi, Kiyoshi Yamaguchi, Emi K. Nishimura, Yoichi Furukawa, Masato Taoka, Chen Hu, Naoki Kaneko, Ryutaro Fukui, Zhiqin Wang, Kensuke Miyake, Shintaro Kawano, Zhigang Cai, Daisuke Koga, Takuma Shibata, Seiji Nakamura, Masafumi Moriyama, Hao-Wen Hsiao, Wei Wei, Yanmei Li, Ryota Sato, Kotono Okabe-Kibe
article en

Abstract

Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome (SS). 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.

International Immunology
Kyushu University (JP), Asahikawa Medical University (JP), Chiba University (JP), Kyushu Dental University (JP), Nagasaki International University (JP), Tianjin Medical University General Hospital (CN), Chiba University Hospital (JP), Institute for Rheumatic Diseases (Japan) (JP), Japan Institute for Advanced Dentistry (JP), Institute of Hematology & Blood Diseases Hospital (CN), Tianjin Medical University (CN), Tokyo Metropolitan University (JP), The University of Tokyo (JP)
Openalex Percentile: Top 53%
Salivary Gland Disorders and Functions
DOISourceOpenAlex
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