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.
Highlights
The mucosal surface of the lower airway is exposed to a vast array of potentially harmful foreign pathogens and antigens derived from inhaled air
Immunofluorescence analysis revealed that glycoprotein 2 (GP2)+ cells reacted with the antiTnfaip2 antibody, the antigen of which was previously shown to be selectively expressed in M cells (Figure 1B) [7, 9]
Tnfaip2 was found throughout the cytoplasm of cells, while GP2 signals occurred on the luminal side of cells and as puncta in the deeper region of the tracheal epithelium (Figures 1A,B)
Summary
The mucosal surface of the lower airway is exposed to a vast array of potentially harmful foreign pathogens and antigens derived from inhaled air. This site, comprising the larynx, trachea, and bronchioles, is lined by the pseudostratified epithelium that comprises mainly of ciliated, goblet, club, tuft, and basal cells. Microfold (M) cells, which are found in the mucosal epithelium associated with lymphoid follicles in the intestine, are one epithelial cell type that specializes in the transport of macromolecules and microorganisms from the intestinal lumen into the subepithelial region via a transepithelial pathway; this process is known as antigen transcytosis [4,5,6]. M-cell-dependent antigen transcytosis may play a key role in the induction of mucosal immune responses, especially in sIgA production, against certain antigens
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