Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

Shunsuke Kimura (), Yutaka Nakamura, Nobuhide Kobayashi, Katsuyuki Shiroguchi, Eiryo Kawakami, Mami Mutoh, Hiromi Takahashi-Iwanaga, Takahiro Yamada, Meri Hisamoto, Midori Nakamura, Nobuyuki Udagawa, Shintaro Sato, Tsuneyasu Kaisho, Toshihiko Iwanaga and Koji Hase ()
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Shunsuke Kimura: Keio University
Yutaka Nakamura: Keio University
Nobuhide Kobayashi: Keio University
Katsuyuki Shiroguchi: PRESTO, Japan Science and Technology Agency
Eiryo Kawakami: RIKEN Medical Sciences Innovation Hub Program (MIH)
Mami Mutoh: Hokkaido University
Hiromi Takahashi-Iwanaga: Hokkaido University
Takahiro Yamada: Keio University
Meri Hisamoto: Hokkaido University
Midori Nakamura: Matsumoto Dental University
Nobuyuki Udagawa: Matsumoto Dental University
Shintaro Sato: Osaka University
Tsuneyasu Kaisho: Wakayama Medical University
Toshihiko Iwanaga: Hokkaido University
Koji Hase: Keio University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-13883-y

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