SLC29A3 disorders are a group of rare genetic disorders caused by mutations in the SLC29A3 gene. Histiocytosis—an immune condition involving phagocyte accumulation in various organs—is the primary manifestation of SLC29A3 disorders. Researchers from Japan have now shown that the aberrant response of the pathogen sensors “toll-like receptor (TLR) 7 and TLR8” directly causes histiocytosis by promoting macrophage proliferation. These findings highlight the potential of TLR7/TLR8 as therapeutic targets for SLC29A3 disorders.
In humans, the SLC29A3 gene regulates the function of lysosomes to control waste recycling in cells such as macrophages (that engulf and destroy foreign bodies). This gene encodes for the lysosomal protein that transport nucleosides — degradation products of RNA and DNA — from lysosomes to the cytoplasm. Loss-of-function mutations in the SLC29A3 gene lead to aberrant nucleoside storage, resulting in a spectrum of conditions called SLC29A3 disorders. These disorders can manifest in the form of pigmented skin patches, enlargement of the liver/spleen, hearing loss, or type 1 diabetes. A key manifestation of this group of disorders is histiocytosis, which is characterized by the accumulation of mononuclear phagocytes (histiocytes) in multiple organs. However, the molecular link between lysosomal nucleoside storage and histiocytosis has remained elusive so far, making the treatment of this condition challenging.
A team of Japanese researchers has now been able to solve this mystery and establish the mechanism underlying SLC29A3 disorders. Their study was published in Volume 220 Issue 9 of Journal of Experimental Medicine on 18 July 2023. The findings clearly describe how the aberrant responses of toll-like receptor (TLR) 7 and TLR8— immune proteins expressed on macrophages — drives histiocytosis under conditions of SLC29A3 loss-of-function. “We have now uncovered how TLR signaling, a key innate immune response pathway, contributes to histiocytosis in SLC29A3 disorders,” remarks Prof. Kensuke Miyake from The Institute of Medical Science, The University of Tokyo, also the corresponding author of the article.
Pathogens engulfed by macrophages are broken down within the lysosomes. The degradation of pathogenic RNA leads to the generation of nucleosides, which can be sensed by TLR7 and TLR8. Given that SLC29A3 mutations lead to abnormal nucleoside storage within lysosomes, the authors hypothesized that the constitutive activation of TLR7 and TLR8 by nucleosides would be involved in SLC29A3 disorders. They tested this hypothesis in mice lacking this gene. While Slc29a3–/– mice showed significant nucleoside accumulation and histiocytosis, the latter phenotype disappeared when the TLR7 gene was knocked out (i.e., in Slc29a3–/– Tlr7–/– mice). This demonstrated that the histiocytosis occurring due to SLC29A3 mutations was dependent on TLR7.
The results also showed that in Slc29a3–/– mice, during excess lysosomal nucleoside storage, TLR7 promoted the proliferation and maturation of a subset of macrophages. Similar findings were observed in patient-derived monocytes with a SLC29A3 mutation. These monocytes showed greater survival and proliferation after stimulation with macrophage colony stimulating factor (M-CSF), a macrophage survival factor, than monocytes derived from healthy subjects . Interestingly, this enhanced survival and proliferation was attenuated when TLR8 was inhibited; human monocytes use TLR8 rather than TLR7 to respond to nucleosides.
Associate Prof. Takuma Shibata, who is also the lead author on this study, explains, “To put it simply, mutations in SLC29A3 lead to nucleoside accumulation in macrophages. These nucleosides activate TLR7 and TLR8, and this excessive TLR response leads to excess macrophage proliferation and accumulation.” Prof. Miyake adds, “In a way, our findings show that SLC29A3 acts as a negative regulator of the TLR7/8 response in cells of the innate immune system.”
The study by the group led by Prof. Miyake and Associate Prof. Shibata answers a long-standing question in the field of innate immunology. “TLR7 and TLR8 could serve as therapeutic targets for SLC29A3 disorders, and this is very promising from the perspective of developing novel therapeutic interventions for these conditions. Moreover, the findings can also pave the way for understanding the pathogenic mechanisms of other disorders associated with macrophage proliferation and accumulation,” Prof. Miyake concludes.
Histiocytosis is a group of disorders characterized by abnormal increases in histiocytes like macrophages
An abnormal response of pathogen sensors in macrophages causes histiocytosis by driving macrophage proliferation
Reference
Journal：
Journal of Experimental Medicine
Title of original paper：
TLR7/8 stress response drives histiocytosis in SLC29A3 disorders
Journal of Experimental Medicine
Title of original paper：
TLR7/8 stress response drives histiocytosis in SLC29A3 disorders
DOI：
10.1084/jem.20230054
Authors：
Takuma Shibata1, Ryota Sato1, Masato Taoka2, Shin-Ichiroh Saitoh1, Mayumi Komine3, Kiyoshi Yamaguchi4, Susumu Goyama5, Yuji Motoi1, Jiro Kitaura6, Kumi Izawa6, Yoshio Yamauchi2, Yumiko Tsukamoto7, Takeshi Ichinohe8, Etsuko Fujita3, Ryosuke Hiranuma1, Ryutaro Fukui1, Yoichi Furukawa4, Toshio Kitamura9, Toshiyuki Takai10, Arinobu Tojo11, Mamitaro Ohtsuki3, Umeharu Ohto12, Toshiyuki Shimizu12, Manabu Ozawa13, Nobuaki Yoshida13, Toshiaki Isobe2, Eicke Latz14, Kojiro Mukai15, Tomohiko Taguchi15, Kensuke Miyake1
Affiliations：
1 Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
2 Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
3 Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
4 Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5 Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan.
6 Atopy Research Center, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
7 Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, 189-0002, Japan.
8 Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
9 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
10 Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
11 Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
12 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan.
13 Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
14 Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany.
15 Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
2 Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
3 Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
4 Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5 Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan.
6 Atopy Research Center, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
7 Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, 189-0002, Japan.
8 Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
9 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
10 Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
11 Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
12 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan.
13 Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
14 Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany.
15 Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
About Dr. Kensuke Miyake
Prof. Kensuke Miyake is a Professor at The Institute of Medical Science, The University of Tokyo. His research interests lie in the areas of innate immunity and autoimmune disease, with a special focus on the molecular machinery regulating these processes. Dr. Miyake is an expert in the field of toll-like receptor signaling and is a member of the Japanese Society for Immunology.UTokyo PEOPLE
Dr. MIYAKE Kensuke
About Dr. Takuma Shibata
Dr. Takuma Shibata is an Associate Professor at The Institute of Medical Science, The University of Tokyo. His research group evaluates the regulatory mechanisms of innate immune responses by pathogen sensors.UTokyo PEOPLE
Dr. Sibata Takuma
Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp/imsut/en/index.html