TLR7/8 stress response drives histiocytosis in SLC29A3 disorders-Reference-Cited by-同舟云学术

TLR7/8 stress response drives histiocytosis in SLC29A3 disorders

Published:2023-07-18 Issue:9 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Shibata Takuma¹^ORCID,Sato Ryota¹^ORCID,Taoka Masato²^ORCID,Saitoh Shin-Ichiroh¹^ORCID,Komine Mayumi³^ORCID,Yamaguchi Kiyoshi⁴^ORCID,Goyama Susumu⁵^ORCID,Motoi Yuji¹^ORCID,Kitaura Jiro⁶^ORCID,Izawa Kumi⁶^ORCID,Yamauchi Yoshio²^ORCID,Tsukamoto Yumiko⁷^ORCID,Ichinohe Takeshi⁸^ORCID,Fujita Etsuko³^ORCID,Hiranuma Ryosuke¹^ORCID,Fukui Ryutaro¹^ORCID,Furukawa Yoichi⁴^ORCID,Kitamura Toshio⁹^ORCID,Takai Toshiyuki¹⁰^ORCID,Tojo Arinobu¹¹^ORCID,Ohtsuki Mamitaro³^ORCID,Ohto Umeharu¹²^ORCID,Shimizu Toshiyuki¹²^ORCID,Ozawa Manabu¹³^ORCID,Yoshida Nobuaki¹³^ORCID,Isobe Toshiaki²^ORCID,Latz Eicke¹⁴^ORCID,Mukai Kojiro¹⁵^ORCID,Taguchi Tomohiko¹⁵^ORCID,Hemmi Hiroaki¹⁶^ORCID,Akira Shizuo¹⁷¹⁸^ORCID,Miyake Kensuke¹^ORCID

Affiliation:

1. The Institute of Medical Science, The University of Tokyo 1 Division of Innate Immunity, Department of Microbiology and Immunology, , Tokyo, Japan

2. Graduate School of Science, Tokyo Metropolitan University 2 Department of Chemistry, , Tokyo, Japan

3. Jichi Medical University 3 Department of Dermatology, , Tochigi, Japan

4. The Institute of Medical Science, The University of Tokyo 4 Division of Clinical Genome Research, , Tokyo, Japan

5. Graduate School of Frontier Sciences, The University of Tokyo 5 Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, , Tokyo, Japan

6. Atopy Research Center, Graduate School of Medicine, Juntendo University 6 , Tokyo, Japan

7. Leprosy Research Center, National Institute of Infectious Diseases 7 Department of Mycobacteriology, , Tokyo, Japan

8. International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo 8 Division of Viral Infection, Department of Infectious Disease Control, , Tokyo, Japan

9. The Institute of Medical Science, The University of Tokyo 9 Division of Cellular Therapy, , Tokyo, Japan

10. Institute of Development, Aging and Cancer, Tohoku University 10 Department of Experimental Immunology, , Sendai, Japan

11. Research Hospital, The Institute of Medical Science, The University of Tokyo 11 Department of Hematology and Oncology, , Tokyo, Japan

12. Graduate School of Pharmaceutical Sciences, The University of Tokyo 12 , Tokyo, Japan

13. Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo 13 , Tokyo, Japan

14. Institute of Innate Immunity, University Hospital Bonn, University of Bonn 14 , Bonn, Germany

15. Laboratory of Organelle Pathophysiology, Graduate School of Life Sciences, Tohoku University 15 Department of Integrative Life Sciences, , Sendai, Japan

16. Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science 16 , Imabari, Japan

17. Laboratory of Host Defense, World Premier Institute—Immunology Frontier Research Center (WPI-IFReC), Osaka University 17 , Osaka, Japan

18. Research Institute for Microbial Diseases (RIMD), Osaka University 18 Department of Host Defense, , Osaka, Japan

Abstract

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3−/− mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3−/− mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

Funder

Japan Society for the Promotion of Science/MEXT KAKENHI

Japan Science and Technology Agency

Japan Agency for Medical Research and Development

Mochida Memorial Foundation for Medical and Pharmaceutical Research

University of Tokyo

University of Tokyo Pandemic Preparedness, Infection and Advanced research Center

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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