Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3

Abstract

Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3−/− mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII−/− mice) were generated by mating TFF3−/− and Fuc-TVII−/− mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII−/−, TFF3−/−, Fuc-TVII−/−, or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3−/− mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3−/− mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/β-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response.

Transmigrating Neutrophils Shape the Mucosal Microenvironment through Localized Oxygen Depletion to Influence Resolution of Inflammation

“…Adherent and fluid mucus layers, secreted by goblet cells, limit physical interaction with luminal bacteria (Johansson et al, 2011). Impaired goblet cell function or mucus layer forming proteins (Muc2, Tff3) have been implicated in the pathogenesis of chronic colonic inflammation (Beck et al, 2010; Van der Sluis et al, 2006). We examined murine epithelial Muc3 and Tff3 , known HIF-dependent gene products, as a proof-of-principle and demonstration that colonic mucus was being affected.…”

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

“…Body weights, stool consistency, and GI bleeding were monitored daily. Clinical scores and colonic damage scores were estimated as detailed previously (49,(70)(71)(72). Colons were collected immediately after sacrifice, and mucosa was scraped to isolate total RNA or proteins.…”

Role of Janus Kinase 3 in Mucosal Differentiation and Predisposition to Colitis

“…Previously, we reported the essential roles of Jak3 in mucosal wound healing and homeostasis (12)(13)(14); here, we determined the effects of Jak3 KO in DSS-induced colitis. Eightweek-old WT and c57/bl jak3 Ϫ/Ϫ mice were given 2.5% (w/v) DSS in drinking water for 9 days using the previously described model (28,29), and the time course of body weight change and parameters for inflammation were determined to measure the induction and severity of colitis. Although the body weight was slightly increased in untreated Jak3 KO mice compared with WT, the body weight decreased progressively in both WT and KO mice following DSS treatment, and the KO mice started showing the signs of illness and severity much earlier than the WT.…”