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

• 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
• Journal Title: Journal of Experimental Medicine
• Volume: Volume 215, Number 2
• Publisher: Rockefeller University Press | 2018-02-01, Pages 501-519
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1084/jem.20160659
• Subjects: Health Sciences, Pathology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Medicine, Research & Experimental; Research & Experimental Medicine; PATCH M CELLS; FACTOR SPI-B; SALMONELLA-TYPHIMURIUM; GENE-EXPRESSION; SELF-TOLERANCE; GROWTH-RATE; PATHWAYS; MICE; DIFFERENTIATION; TRANSCRIPTION

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.