TLR7/8 stress response drives histiocytosis in SLC29A3 disorders
TLR7/8 stress response drives histiocytosis in SLC29A3 disorders
SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm. Loss-of-function mutations in SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6Chi CX3CR1low immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Because accumulated nucleosides primarily originated from cell corpse phagocytosis, TLR7 in immature monocytes recognized nucleoside storage as lysosomal stress and increased phagocyte numbers. This non-inflammatory compensatory response is referred to as the TLR7 stress response where Syk, GSK3beta, Beta-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation. Nucleoside storage failed to induce pro-inflammatory cytokine production in Slc29a3-/- mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6Chi classical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208R SLC29A3 mutation showed higher survival and proliferation in the presence of M-CSF and produced larger amounts of IL-6 upon ssRNA stimulation than did those derived from healthy subjects. A TLR8 antagonist inhibited the survival/proliferation of patient-derived macrophages. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.
Ozawa Manabu、Latz Eicke、Taoka Masato、Yamaguchi Kiyoshi、Tsukamoto Yumiko、Hiranuma Ryosuke、Fukui Ryutaro、Ohtsuki Mamitaro、Ichinohe Takeshi、Shimizu Toshiyuki、Tojo Arinobu、Sato Ryota、Goyama Susumu、Izawa Kumi、Mukai Kojiro、Fujita Etsuko、Yoshida Nobuaki、Kitamura Toshio、Takai Toshiyuki、Isobe Toshiaki、Furukawa Yoichi、Saitoh Shin-Ichiroh、Kitaura Jiro、Motoi Yuji、Komine Mayumi、Shibata Takuma、Yamauchi Yoshio、Taguchi Tomohiko、Miyake Kensuke、Ohto Umeharu
基础医学分子生物学生物化学
Ozawa Manabu,Latz Eicke,Taoka Masato,Yamaguchi Kiyoshi,Tsukamoto Yumiko,Hiranuma Ryosuke,Fukui Ryutaro,Ohtsuki Mamitaro,Ichinohe Takeshi,Shimizu Toshiyuki,Tojo Arinobu,Sato Ryota,Goyama Susumu,Izawa Kumi,Mukai Kojiro,Fujita Etsuko,Yoshida Nobuaki,Kitamura Toshio,Takai Toshiyuki,Isobe Toshiaki,Furukawa Yoichi,Saitoh Shin-Ichiroh,Kitaura Jiro,Motoi Yuji,Komine Mayumi,Shibata Takuma,Yamauchi Yoshio,Taguchi Tomohiko,Miyake Kensuke,Ohto Umeharu.TLR7/8 stress response drives histiocytosis in SLC29A3 disorders[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.10.27.513971.点此复制
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