TY - JOUR
T1 - Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity
AU - Kimura, Shunsuke
AU - Nakamura, Yutaka
AU - Kobayashi, Nobuhide
AU - Shiroguchi, Katsuyuki
AU - Kawakami, Eiryo
AU - Mutoh, Mami
AU - Takahashi-Iwanaga, Hiromi
AU - Yamada, Takahiro
AU - Hisamoto, Meri
AU - Nakamura, Midori
AU - Udagawa, Nobuyuki
AU - Sato, Shintaro
AU - Kaisho, Tsuneyasu
AU - Iwanaga, Toshihiko
AU - Hase, Koji
N1 - Funding Information:
We thank Prof. H. Ohno and Dr. T. Kanaya for valuable suggestions, and Ms. K. Fukuhara for help in performing digital RNA sequencing. This study was supported by JSPS or MEXT Grants-in-Aid for Scientific Research 25460261, 16K08457 (to S.K.), 18H06033 (to Y.N), 16H01369, 17H04089, 18H04680, 25293114, 26116709 (to K.H.), AMED-Crest 16gm0000000h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 (to K.H.), and JST PRESTO JPMJPR19H3 (to S.K.). This study was also supported by grants from the Research Foundation for Opto-Science and Technology, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Food Science Institute Foundation, the SENSHIN Medical Research Foundation (to S.K.), the Takeda Science Foundation (to S.K. and K.H.), the NOVARTIS Foundation JAPAN for Promotion of Science (to K.H.), and the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo (to K.H.).
Funding Information:
1Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo 105-8512, Japan. 2Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. 3PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan. 4Laboratory for Prediction of Cell Systems Dynamics, RIKEN Center for Biosystems Dynamics Research (BDR), Suita 565-0874, Japan. 5Laboratory for Immunogenetics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Japan. 6RIKEN Medical Sciences Innovation Hub Program (MIH), Yokohama 230-0045, Japan. 7Department of Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan. 8Department of Oral Functional Prosthodontics, Division of Oral Functional Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan. 9Department of Biochemistry, Matsumoto Dental University, Nagano 399-0781, Japan. 10Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. 11Mucosal Vaccine Project, BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, Osaka 565-0871, Japan. 12Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan. 13Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan. 14These authors contributed equally: Shunsuke Kimura, Yutaka Nakamura. *email: kimura-sn@pha.keio.ac.jp; hase-kj@pha.keio.ac.jp
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.
AB - Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.
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UR - http://www.scopus.com/inward/citedby.url?scp=85077786078&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13883-y
DO - 10.1038/s41467-019-13883-y
M3 - Article
C2 - 31932605
AN - SCOPUS:85077786078
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 234
ER -