Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7

Shibata, T.; Taoka, M.; Saitoh, S.-I.; Yamauchi, Y.; Motoi, Y.; Komine, M.; Fujita, E.; Sato, R.; Sagara, H.; Ichinohe, T.; Kawazoe, M.; Kato, C.; Furusho, K.; Murakami, Y.; Fukui, R.; Ohtsuki, M.; Ohto, U.; Shimizu, T.; Yoshida, N.; Isobe, T.; MIYAKE, K.

doi:10.1101/2019.12.16.877357

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bioRxiv · 10.1101/2019.12.16.877357

Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7

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Abstract

A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of Slc29a3-/- mice but not Slc29a3-/- Tlr7-/- mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in Slc29a3-/- monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders. One Sentence SummarySLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes.

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Shibata, T., Taoka, M., Saitoh, S.-I., Yamauchi, Y., Motoi, Y., Komine, M., Fujita, E., Sato, R., Sagara, H., Ichinohe, T., Kawazoe, M., Kato, C., Furusho, K., Murakami, Y., Fukui, R., Ohtsuki, M., Ohto, U., Shimizu, T., Yoshida, N., Isobe, T., MIYAKE, K.. 2019-12-16. Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7. https://doi.org/10.1101/2019.12.16.877357

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