Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease

Abstract

TNF plays an integral role in inflammatory bowel disease (IBD) as evidenced by the dramatic therapeutic responses in Crohn’s disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we interrogated the role of TNF signaling on Wnt/β-catenin-mediated intestinal stem and progenitor cell (ISC/PC) expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, ISC/PC Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient (Tnf−/−) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow chimera (BMC) mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IEC. WT-> Tnfr1/2−/− BMC mice given chronic DSS colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in non-transformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Gut IgA abundance in adult life is a major determinant of resistance to dextran sodium sulfate‐colitis and can compensate for the effects of inadequate maternal IgA received by neonates

“…S2) for the inflammatory cytokines interferon-c, IL-17, IL-1b, tumor necrosis factor-a and IL-23, and for the chemokines CXCL1, CCL-19 and CCL-21, which are involved in recruitment of neutrophils, dendritic cells and activated T cells. 12,[27][28][29][30] Both interferona and IL-22 have been reported to have a role in epithelial repair/regeneration and we found lower induction of interferon-a, but higher induction of IL-22 in B6 colonic tissue. No significant induction of IL-6, IL-10, IL-12 and IL-18 was seen in either strain.…”

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

“…15 TNF directly activates bcatenin-dependent transcription in the intestine and promotes epithelial regeneration during colitis. 50 We found that TNF represses SIRT2 expression, suggesting that TNFinduces Wnt/b-catenin signaling in IECs through, at least in part, repression of SIRT2 expression. Our findings provide a direct link between SIRT2 and intestinal inflammation.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…In addition, production of fibroblast growth factor 2 (FGF2) by Treg cells has recently been shown to synergize with IL‐17 to enhance mechanisms of intestinal epithelial repair . IEC responsiveness to tumour necrosis factor also promotes mucosal repair and healing in individuals with Crohn's disease, human cells and mouse models …”

“…109 IEC responsiveness to tumour necrosis factor also promotes mucosal repair and healing in individuals with Crohn's disease, human cells and mouse models. 110 Myeloid cells also play key roles in IEC differentiation and function. For instance, perturbations to macrophage-IEC interactions lead to aberrant differentiation of IEC subtypes.…”