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

Ryodai Shindo; Masaki Ohmuraya; Sachiko Komazawa-Sakon; Sanae Miyake; Yutaka Deguchi; Soh Yamazaki; Takashi Nishina; Takayuki Yoshimoto; Soichiro Kakuta; Masato Koike; Yasuo Uchiyama; Hiroyuki Konishi; Hiroshi Kiyama; Tetuo Mikami; Kenta Moriwaki; Kimi Araki; Hiroyasu Nakano

doi:10.1016/j.isci.2019.05.011

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

iScience. 2019 May 31:15:536-551. doi: 10.1016/j.isci.2019.05.011. Epub 2019 May 14.

Authors

Ryodai Shindo¹, Masaki Ohmuraya², Sachiko Komazawa-Sakon¹, Sanae Miyake¹, Yutaka Deguchi¹, Soh Yamazaki¹, Takashi Nishina¹, Takayuki Yoshimoto³, Soichiro Kakuta⁴, Masato Koike⁵, Yasuo Uchiyama⁴, Hiroyuki Konishi⁶, Hiroshi Kiyama⁶, Tetuo Mikami⁷, Kenta Moriwaki⁸, Kimi Araki⁹, Hiroyasu Nakano¹⁰

Affiliations

¹ Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan.
² Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
³ Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku-ku, Tokyo 160-8402, Japan.
⁴ Department of Cellular Molecular Neuropathology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁵ Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁶ Department of Functional Anatomy and Neuroscience, Graduate School of Medicine, Nagoya University, 65 Tsurumaicho, Showa-ku, Nagoya 466-8560, Japan.
⁷ Department of Pathology, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan.
⁸ Department of Cell Biology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁹ Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
¹⁰ Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan; Host Defense Research Center, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address: hiroyasu.nakano@med.toho-u.ac.jp.

Abstract

A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. Although necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice wherein CFLARs was integrated onto the X chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. Although 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 cells (ILC3s) 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, necroptosis-dependent activation of ILC3s induces lethal ileitis in an IL-22-dependent manner.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Immune Response; Immunology.