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Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis

71 Pages Posted: 10 Feb 2019 Publication Status: Under Review

See all articles by Ryodai Shindo

Ryodai Shindo

Toho University, School of Medicine, Department of Biochemistry

Masaki Ohmuraya

Hyogo College of Medicine - Department of Genetics

Sachiko Komazawa-Sakon

Toho University, School of Medicine, Department of Biochemistry

Sanae Miyake

Toho University, School of Medicine, Department of Biochemistry

Soh Yamazaki

Toho University, School of Medicine, Department of Biochemistry

Takashi Nishina

Toho University, School of Medicine, Department of Biochemistry

Takayuki Yoshimoto

Tokyo Medical University, Institute of Medical Science, Department of Immunoregulation

Soichiro Kakuta

Juntendo University, Graduate School of Medicine, Department of Cellular Molecular Neuropathology

Masato Koike

Juntendo University, Graduate School of Medicine, Department of Cell Biology and Neuroscience

Yasuo Uchiyama

Juntendo University, Graduate School of Medicine, Department of Cellular Molecular Neuropathology

Hiroyuki Konishi

Nagoya University, Graduate School of Medicine, Department of Functional Anatomy and Neuroscience

Hiroshi Kiyama

Nagoya University, Graduate School of Medicine, Department of Functional Anatomy and Neuroscience

Tetuo Mikami

Toho University, School of Medicine, Department of Pathology

Kenta Moriwaki

Osaka University, Graduate School of Medicine, Department of Cell Biology

Kimi Araki

Kumamoto University - Institute of Resource Development and Analysis

Hiroyasu Nakano

Toho University, School of Medicine, Department of Biochemistry; Toho University, School of Medicine, Host Defense Research Center

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Abstract

A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. While necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice where CFLARs was integrated onto the X-chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. While necroptosis was observed in various tissues of CFLARs Tg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion of Ripk3 or Mlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality of CFLARs Tg mice. Type 3 innate lymphoid cell (ILC3)s were activated and recruited to the small intestine along with upregulation of Interleukin 22 (Il22) in CFLARs Tg mice. Deletion of ILC3s or Il22 rescued lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Together, these results reveal an unexpected role for ILC3s in connecting necroptosis and apoptosis.

Keywords: apoptosis, cellular FLICE-inhibitory protein (cFLIP), type 3 innate lymphoid cells (ILC3s), ileitis, Interleukin-22, MLKL, necroptosis, RAR-related orphan receptor gamma t (RORgt), RIPK3, X-chromosome inactivation

Suggested Citation

Shindo, Ryodai and Ohmuraya, Masaki and Komazawa-Sakon, Sachiko and Miyake, Sanae and Yamazaki, Soh and Nishina, Takashi and Yoshimoto, Takayuki and Kakuta, Soichiro and Koike, Masato and Uchiyama, Yasuo and Konishi, Hiroyuki and Kiyama, Hiroshi and Mikami, Tetuo and Moriwaki, Kenta and Araki, Kimi and Nakano, Hiroyasu, Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis (February 8, 2019). Available at SSRN: https://ssrn.com/abstract=3331252 or http://dx.doi.org/10.2139/ssrn.3331252
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ryodai Shindo

Toho University, School of Medicine, Department of Biochemistry

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Masaki Ohmuraya

Hyogo College of Medicine - Department of Genetics

Hyogo
Japan

Sachiko Komazawa-Sakon

Toho University, School of Medicine, Department of Biochemistry

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Sanae Miyake

Toho University, School of Medicine, Department of Biochemistry

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Soh Yamazaki

Toho University, School of Medicine, Department of Biochemistry

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Takashi Nishina

Toho University, School of Medicine, Department of Biochemistry

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Takayuki Yoshimoto

Tokyo Medical University, Institute of Medical Science, Department of Immunoregulation

6-1-1 Shinjuku-ku
Tokyo
Japan

Soichiro Kakuta

Juntendo University, Graduate School of Medicine, Department of Cellular Molecular Neuropathology

2-1-1 Hongo
Bunkyo-ku
Tokyo
Japan

Masato Koike

Juntendo University, Graduate School of Medicine, Department of Cell Biology and Neuroscience

2-1-1 Hongo, Bunkyo-ku
Tokyo
Japan

Yasuo Uchiyama

Juntendo University, Graduate School of Medicine, Department of Cellular Molecular Neuropathology

2-1-1 Hongo
Bunkyo-ku
Tokyo
Japan

Hiroyuki Konishi

Nagoya University, Graduate School of Medicine, Department of Functional Anatomy and Neuroscience

65 Tsurumaicho
Showa-ku
Nagoya
Japan

Hiroshi Kiyama

Nagoya University, Graduate School of Medicine, Department of Functional Anatomy and Neuroscience

65 Tsurumaicho
Showa-ku
Nagoya
Japan

Tetuo Mikami

Toho University, School of Medicine, Department of Pathology

5-21-16 Omori-Nishi
Otaku
Tokyo
Japan

Kenta Moriwaki

Osaka University, Graduate School of Medicine, Department of Cell Biology

2-2 Yamadaoka, Suita
Osaka
Japan

Kimi Araki

Kumamoto University - Institute of Resource Development and Analysis

2-2-1 Honjo
Chuoku
Kumamoto
Japan

Hiroyasu Nakano (Contact Author)

Toho University, School of Medicine, Department of Biochemistry ( email )

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

Toho University, School of Medicine, Host Defense Research Center ( email )

5-21-16 Omori-Nishi
Ota-ku
Tokyo
Japan

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