Reciprocal Expression of Enteric Antimicrobial Proteins in Intestinal Graft-Versus-Host Disease

Abstract

We recently demonstrated that expression of α-defensins, the major antimicrobial peptides produced by Paneth cells, was severely suppressed in mice with graft-versus-host disease (GVHD). In this study, we found that antibacterial lectin, regenerating islet-derived IIIγ (RegIIIγ) was upregulated in villous enterocytes, thus demonstrating the reciprocal control of enteric antimicrobial proteins in GVHD. Upregulation of RegIIIγ was mediated by a mechanism independent upon radiation-induced intestinal tract damage. MyD88-mediated signaling in intestinal epithelium was required for RegIIIγ upregulation in GVHD and antibiotic therapy downregulated RegIIIγ expression. These results suggest that MyD88-mediated sensing of the intestinal microbes disregulated in GVHD induces RegIIIγ upregulation in GVHD and argue a role for RegIIIγ in the pathogenesis of GVHD.

Interleukin-22: Immunobiology and Pathology

“…Reg3β and Reg3γ can be produced by crypt epithelium and mature enterocytes (272). Furthermore, mice with Paneth cell deficiency due to GVHD demonstrate increased expression of Reg3γ, indicating that enterocytes are potent sources of intestinal antimicrobials (273). Additionally, we have found that IL-22R is expressed on Lgr5 + intestinal stem cells (137), although the functional significance of this is unknown.…”

Role of the intestinal mucosa in acute gastrointestinal GVHD

“…Although production of Reg3a and its murine homolog Reg3g have previously been attributed to Paneth cells, it is clear that other non-Paneth-cell IECs produce Reg3g after experimental HCT in mice. 57,63 This potentially explains how Reg3 levels can be elevated despite the loss of Paneth cells that has been observed in the settings of experimental 57,64,65 and clinical 66 GVHD. Importantly, loss of Paneth cells was found to be a poor prognostic finding in clinical cases of intestinal GVHD.…”

Role of the intestinal mucosa in acute gastrointestinal GVHD

“…Why plasma levels of Reg3α correlate with GVHD severity remains an open question, but it may reflect either epithelial cell damage or may be a physiological response to intestinal injury and compromised barrier function. While production of Reg3α and its murine homologue Reg3γ has previously been attributed to Paneth cells, it is clear that other non-Paneth-cell IECs produce Reg3 after experimental BMT in mice 57,63 . This potentially explains how Reg3 levels can be elevated despite the loss of Paneth cells that has been observed in the settings of experimental 57,64,65 and clinical 66 GVHD.…”