Mikami, Yohei

写真a

Affiliation

School of Medicine, Department of Internal Medicine (Gastroenterology and Hepatology) (Shinanomachi)

Position

Associate Professor

External Links

Academic Degrees 【 Display / hide

  • PhD (Medicine), Keio University, Coursework, 2012

 

Research Keywords 【 Display / hide

  • Inflammatory bowel disease

  • Mucosal immunology

  • Tissue regeneration and fibrosis

  • Neuroimmunology

 

Papers 【 Display / hide

  • CD8<sup>+</sup> tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells

    Koda Y., Teratani T., Chu P.S., Hagihara Y., Mikami Y., Harada Y., Tsujikawa H., Miyamoto K., Suzuki T., Taniki N., Sujino T., Sakamoto M., Kanai T., Nakamoto N.

    Nature Communications (Nature Communications)  12 ( 1 ) 4474 2021.12

    ISSN  2041-1723

     View Summary

    Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103−CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

  • Pathogenesis and management of gastrointestinal inflammation and fibrosis: from inflammatory bowel diseases to endoscopic surgery

    Iwata K., Mikami Y., Kato M., Yahagi N., Kanai T.

    Inflammation and Regeneration (Inflammation and Regeneration)  41 ( 1 ) 21 2021.12

    ISSN  1880-9693

     View Summary

    Gastrointestinal fibrosis is a state of accumulated biological entropy caused by a dysregulated tissue repair response. Acute or chronic inflammation in the gastrointestinal tract, including inflammatory bowel disease, particularly Crohn’s disease, induces fibrosis and strictures, which often require surgical or endoscopic intervention. Recent technical advances in endoscopic surgical techniques raise the possibility of gastrointestinal stricture after an extended resection. Compared to recent progress in controlling inflammation, our understanding of the pathogenesis of gastrointestinal fibrosis is limited, which requires the development of prevention and treatment strategies. Here, we focus on gastrointestinal fibrosis in Crohn’s disease and post-endoscopic submucosal dissection (ESD) stricture, and we review the relevant literature.

  • MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

    Wigton E.J., Mikami Y., McMonigle R.J., Castellanos C.A., Wade-Vallance A.K., Zhou S.K., Kageyama R., Litterman A., Roy S., Kitamura D., Dykhuizen E.C., Allen C.D.C., Hu H., O’Shea J.J., Ansel K.M.

    Journal of Experimental Medicine (Journal of Experimental Medicine)  218 ( 11 )  2021.09

    ISSN  00221007

     View Summary

    MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.

  • Epithelium Replacement Contributes to Field Expansion of Squamous Epithelium and Ulcerative Colitis-Associated Neoplasia.

    Sugimoto S, Iwao Y, Shimoda M, Takabayashi K, Sato T, Kanai T, Keio IBD Collaborators Contributors., Mutaguchi M, Nanki K, Okabayashi K, Kawaida M, Aoki Y, Yoshimatsu Y, Kiyohara H, Kawaguchi T, Mikami Y, Fukuhara K, Sujino T, Hosoe N, Ogata H, Yahagi N

    Gastroenterology  2021.09

    ISSN  0016-5085

  • Hepatic Adenosine Triphosphate Reduction Through the Short-Chain Fatty Acids–Peroxisome Proliferator-Activated Receptor γ–Uncoupling Protein 2 Axis Alleviates Immune-Mediated Acute Hepatitis in Inulin-Supplemented Mice

    Yamaguchi A., Teratani T., Chu P.s., Suzuki T., Taniki N., Mikami Y., Shiba S., Morikawa R., Amiya T., Aoki R., Kanai T., Nakamoto N.

    Hepatology Communications (Hepatology Communications)  5 ( 9 ) 1555 - 1570 2021.09

     View Summary

    How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferon-γ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γ-type peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA–PPARγ–UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA–PPARγ–UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • Primary granulocytic sarcoma of the small intestine diagnosed by single-balloon enteroscopy: A case report

    Ono K., Mikami Y., Hosoe N.

    Digestive Endoscopy (Digestive Endoscopy)  32 ( 3 ) 436 - 436 2020.03

    ISSN  09155635

  • Innate lymphoid cells in organ fibrosis

    Mikami Y., Takada Y., Hagihara Y., Kanai T.

    Cytokine and Growth Factor Reviews (Cytokine and Growth Factor Reviews)  42   27 - 36 2018.08

    ISSN  13596101

     View Summary

    © 2018 Elsevier Ltd Innate lymphoid cells (ILCs) are a recently identified family of lymphoid effector cells. ILCs are mainly clustered into 3 groups based on their unique cytokine profiles and transcription factors typically attributed to the subsets of T helper cells. ILCs have a critical role in the mucosal immune response through promptly responding to pathogens and producing large amount of effector cytokines of type 1, 2, or 3 responses. In addition to the role of early immune responses against infections, ILCs, particularly group 2 ILCs (ILC2), have recently gained attention for modulating remodeling and fibrosis especially in the mucosal tissues. Herein, we overview the current knowledge in this area, highlighting roles of ILCs on fibrosis in the mucosal tissues, especially focusing on the gut and lung. We also discuss some new directions for future research by extrapolating from knowledge derived from studies on Th cells.

  • GoldiRunx and Remembering Cytotoxic Memory

    Mikami Y., Kanno Y.

    Immunity (Immunity)  48 ( 4 ) 614 - 615 2018.04

    ISSN  10747613

     View Summary

    © 2018 The molecular basis for T cell memory differentiation remains elusive. Wang et al. (2018) identify Runx3 as an initiating transcription factor that specifies regulatory regions required for cytotoxic T cell (CTL) memory differentiation early after TCR signaling and constrains the ability of T-bet to drive terminal effector generation. The molecular basis for T cell memory differentiation remains elusive. Wang et al. (2018) identify Runx3 as an initiating transcription factor that specifies regulatory regions required for cytotoxic T cell (CTL) memory differentiation early after TCR signaling and constrains the ability of T-bet to drive terminal effector generation.

Presentations 【 Display / hide

  • RESIDENT NON-CLASSICAL MONOCYTES ARE CRITICALLY IMPORTANT FOR TISSUE DESTRUCTION IN ARTHRITIS

    Puchner, Antonia, Saferding, Victoria, Bonelli, Michael, Mikami, Yohei, Goncalves-Alves, Eliana, Binder, Nikolaus B., Steiner, Carl-Walter, Hayer, Silvia, Niederreiter, Birgit, Koenders, Marije M., Smolen, Josef S., Redlich, Kurt, Bluml, Stephan

    ANNALS OF THE RHEUMATIC DISEASES, 2017.03

Research Projects of Competitive Funds, etc. 【 Display / hide

  • Elucidation of the entropy of tissue damage in digestive organs and development of new therapeutic approaches

    2021.08
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 三上 洋平, Grant-in-Aid for Transformative Research Areas (B), Principal Investigator

  • Gene regulation in the gut T cells and IBD

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 三上 洋平, Grant-in-Aid for Scientific Research (B), Principal Investigator

     View Summary

    炎症性腸疾患(IBD)は、難治性の慢性腸管炎症性疾患である。依然として根治術は存在せず、多くの分子標的療法が臨床応用されているものの、不十分な効果や、感染症をはじめとした副作用が依然として大きな問題である。本研究では、多数の分子を標的として細胞内シグナルを調整するmiRNAに着目し、IBDの病態に関与する腸管免疫細胞特異的な新規炎症惹起性パスウェイを同定し、新規IBD治療法の開発を目指す。

  • 宿主侵入菌に対する腸管免疫応答を介した消化器免疫難病の病態解明

    2020.04
    -
    2023.03

    Keio University, 金井 隆典, 寺谷 俊昭, 三上 洋平, Grant-in-Aid for Scientific Research (A)

     View Summary

    本研究課題は、免疫機能異常が病因とされる免疫疾患群において、病変の首座を「病態の発症臓器」ではなく、「細菌が感染したリンパ節」とし、その病態形成機序の本質に迫ることである。PSCを代表例として、免疫難病において、(1)疾患特異的な体内侵入性細菌による腸管上皮破壊、(2)細菌の侵入ルートとリンパ節への感染、(3)リンパ節での免疫応答、(4)腸管外臓器への免疫細胞蓄積メカニズム、(5)クローン病における生体内侵入腸内細菌による免疫疾患の病態の本質に迫る。さらに、(6)疾患特異的な侵入性細菌を特異的に排除するファージ療法の開発に繋げることを課題とする。

  • 腸管Tリンパ球における体内時計と増殖代謝

    2019.04
    -
    2022.03

    Keio University, 木内 謙一郎, 土居 雅夫, 宮下 和季, 三上 洋平, Grant-in-Aid for Scientific Research (C)

     View Summary

    本研究はT細胞が活性化する際の増殖代謝と体内時計の関与を検討する事で、体内時計の免疫機能における重要性を探索し、炎症性腸疾患や大腸癌、肥満や糖尿病などの根底に存在する新しい病態生理や新たな創薬の標的を発見することを目的としている。国内外の幅広い研究者と共同で研究を展開して行く他、RNA-seqやChIP-seqなどの網羅的な解析手法を導入することで、概日リズムと細胞増殖代謝の全体像の把握と両者の関係性を幅広く追求することを本研究の特色とする。

Awards 【 Display / hide

  • 第55回日本消化器免疫学会総会 奨励賞

    2018.12

    Type of Award: Awards of National Conference, Council and Symposium

  • 三四会奨励賞

    2011, Keio University School of Medicine, Sanshikai

    Type of Award: Keio commendation etc.

 

Courses Taught 【 Display / hide

  • CLINICAL IMMUNOLOGY

    2021

  • CLINICAL IMMUNOLOGY

    2020