| Autor: |
Takuma Shibata, Ryota Sato, Masato Taoka, Shin-Ichiroh Saitoh, Mayumi Komine, Kiyoshi Yamaguchi, Susumu Goyama, Yuji Motoi, Jiro Kitaura, Kumi Izawa, Yoshio Yamauchi, Yumiko Tsukamoto, Takeshi Ichinohe, Etsuko Fujita, Ryosuke Hiranuma, Ryutaro Fukui, Yoichi Furukawa, Toshio Kitamura, Toshiyuki Takai, Arinobu Tojo, Mamitaro Ohtsuki, Umeharu Ohto, Toshiyuki Shimizu, Manabu Ozawa, Nobuaki Yoshida, Toshiaki Isobe, Eicke Latz, Kojiro Mukai, Tomohiko Taguchi, Kensuke Miyake |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.10.27.513971 |
| Popis: |
SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm1. Loss-of-function mutations inSLC29A3cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs2,3. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis inSlc29a3−/−mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides4,5. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6ChiCX3CR1lowimmature monocytes and their maturation into Ly6Clowphagocytes inSlc29a3−/−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, GSK3β, β-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation6,7. Nucleoside storage failed to induce pro-inflammatory cytokine production inSlc29a3−/−mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6Chiclassical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208RSLC29A3mutation 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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