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Front Immunol. 2019 Jun 11;10:1323. doi: 10.3389/fimmu.2019.01323. eCollection 2019.

Airway M Cells Arise in the Lower Airway Due to RANKL Signaling and Reside in the Bronchiolar Epithelium Associated With iBALT in Murine Models of Respiratory Disease.

Author information

1
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
2
Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
3
Department of Orthodontics, Faculty of Dental Medicine, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
4
Division of Oral Functional Science, Department of Oral Functional Prosthodontics, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
5
School of Medicine, Hokkaido University, Sapporo, Japan.
6
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Abstract

Microfold (M) cells residing in the follicle-associated epithelium of mucosa-associated lymphoid tissues are specialized for sampling luminal antigens to initiate mucosal immune responses. In the past decade, glycoprotein 2 (GP2) and Tnfaip2 were identified as reliable markers for M cells in the Peyer's patches of the intestine. Furthermore, RANKL-RANK signaling, as well as the canonical and non-canonical NFκB pathways downstream, is essential for M-cell differentiation from the intestinal stem cells. However, the molecular characterization and differentiation mechanisms of M cells in the lower respiratory tract, where organized lymphoid tissues exist rarely, remain to be fully elucidated. Therefore, this study aimed to explore M cells in the lower respiratory tract in terms of their specific molecular markers, differentiation mechanism, and functions. Immunofluorescence analysis revealed a small number of M cells expressing GP2, Tnfaip2, and RANK is present in the lower respiratory tract of healthy mice. The intraperitoneal administration of RANKL in mice effectively induced M cells, which have a high capacity to take up luminal substrates, in the lower respiratory epithelium. The airway M cells associated with lymphoid follicles were frequently detected in the pathologically induced bronchus-associated lymphoid tissue (iBALT) in the murine models of autoimmune disease as well as pulmonary emphysema. These findings demonstrate that RANKL is a common inducer of M cells in the airway and digestive tracts and that M cells are associated with the respiratory disease. We also established a two-dimensional culture method for airway M cells from the tracheal epithelium in the presence of RANKL successfully. This model may be useful for functional studies of M cells in the sampling of antigens at airway mucosal surfaces.

KEYWORDS:

GP2; M cells; RANKL; iBALT; lower airway; microfold cells

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