Browsing by Author "Mukai, Tomoyuki"

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    Editorial: A new frontier in translational research on autoinflammatory diseases - various aspects of innate immunity on human diseases
    (Frontiers Media, 2023-01-31) Mukai, Tomoyuki; Ida, Hiroaki; Ueki, Yasuyoshi; Nishikomori, Ryuta; Biomedical Sciences and Comprehensive Care, School of Dentistry
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    Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model
    (Wiley, 2021) Mukai, Tomoyuki; Akagi, Takahiko; Hiramatsu Asano, Sumie; Tosa, Ikue; Ono, Mitsuaki; Kittaka, Mizuho; Ueki, Yasuyoshi; Yahagi, Ayano; Iseki, Masanori; Oohashi, Toshitaka; Ishihara, Katsuhiko; Morita, Yoshitaka; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Objective Cherubism is a genetic disorder characterised by bilateral jawbone deformation. The associated jawbone lesions regress after puberty, whereas severe cases require surgical treatment. Although several drugs have been tested, fundamental treatment strategies for cherubism have not been established. The effectiveness of imatinib has recently been reported; however, its pharmaceutical mechanism remains unclear. In this study, we tested the effects of imatinib using a cherubism mouse model. Methods We used Sh3bp2 P416R cherubism mutant mice, which exhibit systemic organ inflammation and osteopenia. The effects of imatinib were determined using primary bone marrow-derived macrophages. Imatinib was administered intraperitoneally to the mice, and serum tumour necrosis factor-α (TNFα), organ inflammation and bone properties were examined. Results The cherubism mutant macrophages produced higher levels of TNFα in response to lipopolysaccharide compared to wild-type macrophages, and imatinib did not significantly suppress TNFα production. Although imatinib suppressed osteoclast formation in vitro, administering it in vivo did not suppress organ inflammation and osteopenia. Conclusion The in vivo administration of imatinib had a minimal therapeutic impact in cherubism mutant mice. To establish better pharmaceutical interventions, it is necessary to integrate new findings from murine models with clinical data from patients with a definitive diagnosis of cherubism.
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    SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus
    (MDPI, 2021-04-17) Kawahara, Kyoko; Mukai, Tomoyuki; Iseki, Masanori; Nagasu, Akiko; Nagasu, Hajime; Akagi, Takahiko; Tsuji, Shoko; Hiramatsu-Asano, Sumie; Ueki, Yasuyoshi; Ishihara, Katsuhiko; Kashihara, Naoki; Morita, Yoshitaka; Medicine, School of Medicine
    Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.
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    Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice
    (MDPI, 2019-04-30) Nagasu, Akiko; Mukai, Tomoyuki; Iseki, Masanori; Kawahara, Kyoko; Tsuji, Shoko; Nagasu, Hajime; Ueki, Yasuyoshi; Ishihara, Katsuhiko; Kashihara, Naoki; Morita, Yoshitaka; Biomedical Sciences and Comprehensive Care, School of Dentistry
    SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.