Expression of the ATP-gated P2X₇ Receptor on M Cells and Its Modulating Role in the Mucosal Immune Environment

Abstract

Interactions between microbes and epithelial cells in the gastrointestinal tract are closely associated with regulation of intestinal mucosal immune responses. Recent studies have highlighted the modulation of mucosal immunity by microbe-derived molecules such as ATP and short-chain fatty acids. In this study, we undertook to characterize the expression of the ATP-gated P2X7 receptor (P2X7R) on M cells and its role in gastrointestinal mucosal immune regulation because it was poorly characterized in Peyer's patches, although purinergic signaling via P2X7R and luminal ATP have been considered to play an important role in the gastrointestinal tract. Here, we present the first report on the expression of P2X7R on M cells and characterize the role of P2X7R in immune enhancement by ATP or LL-37.

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

“…Unexpectedly, BBG increased mP2rx7 expression in the gastrointestinal tract. Given that cellular infiltrates in the duodenum were minimal and similar between groups, this increase in mP2rx7 expression may represent BBG blockade of ATP-mediated death of P2X7-expressing host cells such as intestinal epithelial cells (52) , M cells (53) or myenteric plexus neurons (54) . This notion is indirectly supported by BBG impairing molecular development of gastrointestinal GVHD as evidenced by reduced mReg3g expression in the duodenum.…”

The development of mucosal vaccines for both mucosal and systemic immune induction and the roles played by adjuvants

“…GP2, a protein expressed specifically by M cells, drives transcytosis of FimH+ bacteria into such cells. Therefore, M cell-specific markers can be utilized for antigen delivery to mucosal immune inductive sites [ 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 ] ( Table 4 ). For example, an M cell-specific antibody, NKM 16-2-4, recognizes the α(1,2)-fucose-containing carbohydrate moiety of M cells and can be used to enhance delivery of an associated antigen [ 33 ].…”

“…Finally, cathelicidin LL-37 is an immunostimulatory adjuvant that targets antigens to M cells. LL-37 increases antigen delivery to such cells and activates FDCs by interacting with the formyl peptide receptor 2 [ 24 ]. This enhances the induction of antigen-specific immune responses in both the systemic and mucosal compartments.…”

The P2X7 receptor in mucosal adaptive immunity

“…They are also exploited by several invasive pathogens as portal for systemic infection. Interestingly, P2X7R was shown to be expressed at the apical site of M cells, suggesting luminal eATP could have a role in regulating the transcellular transport of intestinal content across the mucosal barrier into GALT and/or the expression of innate immune response genes by M cells via P2X7R signaling [ 40 ]. In addition to transcytosis via M cells, other mechanisms have been shown to allow sampling of the intestinal luminal content independently of organized lymphoid tissue.…”