Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8

Abstract

<jats:p>Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.</jats:p>

Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage

“…LYPD8 binds to flagellated bacteria such as Escherichia coli and prevents bacterial translocation by inhibiting bacterial motility. Based on these findings, we studied the protective role of LYPD8 in murine GVHD using LYPD8-deficient mice as recipients (2). First, we found that disruption of the inner mucus layer in allogeneic recipients led to disappearance of the LYPD8-rich layer in the mucus layer.…”

“…However, GVHD leads to a reduction in intestinal goblet cells, which results in disruption of the mucus layer due to its rapid turnover (Figure 2 and Table 1); the mucus layer is renewed every 1 to 2 hours by newly produced mucus from goblet cells (151)(152)(153). Recently, we studied the role of goblet cells and the inner mucus layer in the pathophysiology of acute GVHD using mouse models of acute GVHD (2). First, we confirmed that goblet cells were profoundly and persistently reduced in the colon after allo-SCT, which led to disruption of the colonic twolayered mucus system in allogeneic recipients in association with enhanced bacterial translocation, elevated plasma levels of proinflammatory cytokines, and exacerbation of GVHD.…”

“…In the steady state and after parasite infections, ILC2s produce growth factors of goblet cells, such as interleukin 13 (IL-13), in response to interleukin-25 (IL-25) secreted from Tuft cells (17,18). We found that pretransplant administration of IL-25 expanded goblet cells that persisted after GVHD, preventing bacterial translocation, elevation of proinflammatory cytokines, and exacerbation of GVHD (2). Conditioning TBI and chemotherapy lead to prolonged depletion of ILC2s in mice and humans (3,4), which could further reduce goblet cells or impair regeneration of these cells.…”

The post-hematopoietic cell transplantation microbiome: relationships with transplant outcome and potential therapeutic targets

“…It was recently described that stimulation of goblet cells via IL-25 could prevent bacterial translocation and dampened inflammation in an experimental acute GvHD model. 65 Exogenous supplementation of butyrate or indoles was also able to enhance epithelial integrity and mitigate acute GvHD in experimental mouse models whereas deletion of the SCFA receptor GPR43 increased acute GvHD. [66][67][68] However, butyrate can have opposite effects and may delay mucosal wound repair by inhibiting proliferation of intestinal epithelial stem/progenitor cells in a dose-dependent manner.…”

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

“…Administration of GLP-2 promoted regeneration of ISCs and Paneth cells and restored intestinal homeostasis, resulting in amelioration of GVHD ( 141 ). IL-25 protects Goblet cells and also could improve transplant outcome ( 125 ). ISCs and Paneth cells express IFN- γ receptors.…”