KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2011.04

  -

  2016.03

  京都大学医学研究科, 特定准教授

• 2016.04

  -

  2017.03

  慶應義塾大学医学部, 薬理学, 講師

• 2017.04

  -

  Present

  慶應義塾大学医学部, 薬理学, 准教授

Licenses and Qualifications 【 Display / hide 】

Licenses and Qualifications 【 Display / hide 】

• 薬剤師

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.

  Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma

  EMBO reports  2026.04

  Last author, Corresponding author,  ISSN  1469-221X

  　View Summary

  Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes. In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.

  • Access to Document (DOI)

• Aquaporin 3 inhibition attenuates imiquimod-induced psoriatic symptoms in a murine model.

  Ryosuke Okubo, Manami Tanaka, Akiharu Kubo, Masato Yasui, Mariko Hara-Chikuma

  Molecular biology reports 52 ( 1 ) 354 - 354 2025.04

  Last author, Corresponding author,  ISSN  0301-4851

  　View Summary

  BACKGROUND: Aquaporin 3 (AQP3) is highly expressed in both keratinocytes and T cells within psoriatic skin. Previous studies have demonstrated that AQP3 knockout mice show reduced development of psoriatic symptoms in murine models. This study aims to evaluate the effect of AQP3 inhibition on psoriasis progression. METHODS AND RESULTS: AQP3 conditional knockout mice were generated to assess the role of AQP3 expression in keratinocytes and T cells in psoriasis pathogenesis. In an imiquimod (IMQ)-induced psoriasis model, psoriatic symptoms were significantly reduced in mice with keratinocyte-specific AQP3 deletion. Additionally, AQP3 inhibition by administration of anti-AQP3 monoclonal antibody (mAb) effectively alleviated IMQ-induced psoriasis symptoms in wild-type mice. CONCLUSIONS: AQP3 inhibition presents a promising approach for the treatment of psoriasis.

  • Access to Document (DOI)

• HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.

  Lingjia Hong, Manami Tanaka, Masato Yasui, Mariko Hara-Chikuma

  Scientific reports 14 ( 1 ) 22541 - 22541 2024.09

  Last author, Corresponding author

  　View Summary

  Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.

  • Access to Document (DOI)

• Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination.

  Kensuke Sato, Mariko Hara-Chikuma, Masato Yasui, Joe Inoue, Yun-Gi Kim

  iScience 27 ( 6 ) 109903 - 109903 2024.06

  Accepted

  　View Summary

  Water is the most abundant substance in the human body and plays a pivotal role in various bodily functions. While underhydration is associated with the incidence of certain diseases, the specific role of water in gut function remains largely unexplored. Here, we show that water restriction disrupts gut homeostasis, which is accompanied by a bloom of gut microbes and decreased numbers of immune cells, especially Th17 cells, within the colon. These microbial and immunological changes in the gut are associated with an impaired ability to eliminate the enteric pathogen Citrobacter rodentium. Moreover, aquaporin 3, a water channel protein, is required for the maintenance of Th17 cell function and differentiation. Taken together, adequate water intake is critical for maintaining bacterial and immunological homeostasis in the gut, thereby enhancing host defenses against enteric pathogens.

  • Access to Document (DOI)

• Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition.

  By Yukiko Tokifuji, Hodaka Hayabuchi, Takashi Sasaki, Mariko Hara-Chikuma, Keiji Hirota, Hayato Takahashi, Masayuki Amagai, Akihiko Yoshimura, Shunsuke Chikuma

  iScience 27 ( 1 ) 108646 - 108646 2024.01

  Accepted

  　View Summary

  IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype T cells while allowing the survival and proliferation of IL-7R+ memory-phenotype cells. The surviving IL-7R+ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R+ Th17 cells in vivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases.

  • Access to Document (DOI)

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Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• AQP3 expression in keratinocytes is involved in hyperplasia in atopic dermatitis

  Kyoko Nakahigashi, Kenji Kabashima, Akihiko Ikoma, Yoshiki Miyachi, Mariko Hara-Chikuma

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 130   S23 - S23 2010.09

  ISSN  0022-202X

• A controlled aquaporin-3 expression in T lymphocytes regulate their migration and trafficking in cutaneous immune reaction

  M. Hara-Chikuma, S. Chikuma, K. Kabashima, K. Nakahigashi, A. Kamegawa, Y. Fujiyoshi, A. S. Verkman, Y. Sugiyama, S. Inoue, Y. Miyachi

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 130   S116 - S116 2010.04

  ISSN  0022-202X

• Flaky tail mouse as a possible model of atopic dermatitis

  C. Moniaga, M. Chikuma, H. Kawasaki, S. Nakajima, H. Tanizaki, G. Egawa, T. Honda, M. Amagai, Y. Miyachi, K. Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 129   S56 - S56 2009.09

  ISSN  0022-202X

• FLAKY TAIL MOUSE AS A POSSIBLE MODEL OF ATOPIC DERMATITIS: PRURITUS-ASSOCIATED RESPONSE INDUCED IN FLAKY TAIL MOUSE

  Catharina Sagita Moniaga, Gyohei Egawa, Hiroshi Kawasaki, Mariko Hara Chikuma, Tetsuya Honda, Hideaki Tanizaki, Saeko Nakajima, Yoshiki Tokura, Yoshiki Miyachi, Masayuki Amagai, Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA 89 ( 6 ) 695 - 695 2009

  ISSN  0001-5555

• A GPI anchor is required for the epidermal permeability barrier

  S Inoue, M Hara, J Takeda, M Tarutani, Y Uchida, P Elias, W Holleran

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 117 ( 2 ) 415 - 415 2001.08

  ISSN  0022-202X

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

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

• 低湿度ストレスが関与する皮膚病態制御メカニズムの解明と治療戦略の探索

  2024.04

  -

  2027.03

  基盤研究(B), Principal investigator

• Involvement of aquaporin-3 in cancer progression

  2021.04

  -

  2024.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

• Role of Aquaporin mediated H2O2 in inflammatory skin disease

  2016.04

  -

  2018.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• PHARMACOLOGY

  2026

• PHARMACOLOGY

  2025

• PHARMACOLOGY

  2024

• PHARMACOLOGY

  2023

• PHARMACOLOGY

  2022

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Courses Previously Taught 【 Display / hide 】

Courses Previously Taught 【 Display / hide 】

• 薬理学

  Keio University

  2016.04

  -

  Present

  , 

  Undergraduate (specialized), Seminar