Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-kappa B signaling

• Type of Material: Article
• Authors: Takashi Kanaya, RIKEN Center for Integrative Medical Sciences; Sayuri Sakakibara, RIKEN Center for Integrative Medical Sciences; Toshi Jinnohara, RIKEN Center for Integrative Medical Sciences; Masami Hachisuka, RIKEN Center for Integrative Medical Sciences; Naoko Tachibana, RIKEN Center for Integrative Medical Sciences; Shinya Hidano, Oita University; Takashi Kobayashi, Oita University; Shunsuke Kimura, Hokkaido University; Toshihiko Iwanaga, Hokkaido University; Tomoo Nakagawa, Chiba University; Tatsuro Katsuno, Chiba University; Naoya Kato, Chiba University; Taishin Akiyama, RIKEN Center for Integrative Medical Sciences; Toshiro Sato, Keio University; Ifor Williams, Emory University; Hiroshi Ohno, RIKEN Center for Integrative Medical Sciences
• Language: English
• Date: 2018-02-01
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Kanaya et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20160659
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 215
• Issue: 2
• Start Page: 501
• End Page: 519
• Grant/Funding Information: This work was supported in part by the Japan Society for the Promotion of Science KAKENHI (grant 26460584 to T. Kanaya and grant 24249029 to H. Ohno), Ministry of Education, Culture, Sports, Science and Technology KAKENHI (grant 15H01165 to T. Kanaya and grant 20113003 to H. Ohno), Uehara Memorial Foundation (grant to T. Kanaya), Takeda Science Foundation (grant to T. Kanaya), and Mochida Memorial Foundation for Medical and Pharmaceutical Research (grant to T.K.).
• Keywords: GENE-EXPRESSION; SELF-TOLERANCE; Medicine, Research & Experimental; SALMONELLA-TYPHIMURIUM; Immunology; Science & Technology; Research & Experimental Medicine; MICE; PATHWAYS; DIFFERENTIATION; PATCH M CELLS; FACTOR SPI-B; GROWTH-RATE; TRANSCRIPTION; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor-associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.