Research ArticleDermatologyImmunology Open Access | 10.1172/JCI171088

Satoshi Nakamizo,1,2 Yuki Sugiura,3 Yoshihiro Ishida,1 Yoko Ueki,4 Satoru Yonekura,1 Hideaki Tanizaki,4 Hiroshi Date,5 Akihiko Yoshizawa,6 Teruasa Murata,7 Kenji Minatoya,8 Mikako Katagiri,9 Seitaro Nomura,9,10 Issei Komuro,10,11 Seishi Ogawa,12,13 Saeko Nakajima,1,14 Naotomo Kambe,1 Gyohei Egawa,1 and Kenji Kabashima1,15

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Nakamizo, S. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Sugiura, Y. in: JCI | PubMed | Google Scholar |

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Ishida, Y. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Ueki, Y. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Yonekura, S. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Tanizaki, H. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Date, H. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Yoshizawa, A. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Murata, T. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Minatoya, K. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Katagiri, M. in: JCI | PubMed | Google Scholar |

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Nomura, S. in: JCI | PubMed | Google Scholar |

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Komuro, I. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Ogawa, S. in: JCI | PubMed | Google Scholar |

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Nakajima, S. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Kambe, N. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Egawa, G. in: JCI | PubMed | Google Scholar

1Department of Dermatology,

2Alliance Laboratory for Advanced Medical Research, and

3Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

4Department of Dermatology, Kansai Medical University, Osaka, Japan.

5Department of Thoracic Surgery and

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

7Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

8Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

9Department of Cardiovascular Medicine and

10Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo.

11International University of Health and Welfare, Tokyo, Japan.

12Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

13Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.

14Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.

15Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), Singapore.

Address correspondence to: Satoshi Nakamizo, Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto 606-8507, Japan. Phone: 81.75.751.3310; Email: s.nakami@kuhp.kyoto-u.ac.jp. Or to: Kenji Kabashima, Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building, Biopolis, 138648 Singapore. Phone: 65.6407.0011; Email: kaba@kuhp.kyoto-u.ac.jp.

Find articles by Kabashima, K. in: JCI | PubMed | Google Scholar

Published December 1, 2023 - More info

Published in Volume 133, Issue 23 on December 1, 2023
J Clin Invest. 2023;133(23):e171088. https://doi.org/10.1172/JCI171088.
© 2023 Nakamizo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published December 1, 2023 - Version history
Received: April 3, 2023; Accepted: September 27, 2023 View PDF Abstract

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2–positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

Graphical Abstract Introduction

Granulomas are chronic inflammatory lesions having well-defined borders and comprising mainly macrophages and other inflammatory cells (1). Differentiation of macrophages into epithelioid cells and multinucleated giant cells is often observed. Sarcoidosis is a typical granulomatosis disease in which granulomas usually develop in organs throughout the body, including the skin, lungs, lymph nodes, heart, and eyes (2). Sarcoidosis may resolve within a few years without treatment, but can persist for decades (3). In severe cases, sarcoidosis can lead to pulmonary fibrosis, blindness, and heart failure. An analysis of the economic impact of sarcoidosis in the United States indicates a significant burden, as evidenced by the total annual health-care costs incurred by commercial payers per patient within the first year after diagnosis, which is approximately $19,714 (4). In addition to symptomatic treatment with steroids, treatment with TNF-α–neutralizing antibodies and Janus kinase inhibitors has been considered for sarcoidosis (2, 5, 6). However, these therapies have significant side effects, such as immunosuppression. Novel therapeutic directions are, therefore, urgently needed.

Uncovering the pathogenesis of sarcoidosis is essential to developing specific therapies. Granuloma typically manifests as a reaction to exogenous foreign bodies that have been left undigested for a long period of time (1). Compared with nonfused macrophages, giant cells generally show enhanced levels of ROS and acid production that together contribute to the rejection of foreign substances and microorganisms (7,