Resistin-Like Molecule β (RELMβ/FIZZ2) Is Highly Expressed in the Ileum of SAMP1/YitFc Mice and Is Associated with Initiation of Ileitis

Abstract

SAMP1/Fc mice develop spontaneous ileitis that shares many features with human Crohn’s disease. One of the earliest features of ileitis in SAMP1/Fc mice is an increase in the number of ileal goblet and intermediate cells. Resistin-like molecule β (RELMβ) is a goblet cell-specific, cysteine-rich peptide previously shown to function as part of the innate immune response. In this study, we examined the role of expression of RELMβ in the initiation of ileal inflammation in SAMP1/Fc mice. RELMβ was highly induced in the ilea of SAMP1/Fc mice beginning at age 5 wk, coincident with the histological appearance of inflammation. RELMβ was found in ileal goblet cells and some intermediate and Paneth cells. Surprisingly, RELMβ mRNA levels were significantly increased in the ilea of 80% of germ-free SAMP1/Fc mice examined compared with specific pathogen-free AKR control mice of similar age. Ileitis was observed in germfree SAMP1/Fc mice, although it was attenuated relative to specific pathogen-free SAMP1/Fc mice. These data suggest that neither the early induction of RELMβ expression nor ileal inflammation requires the presence of viable intestinal flora. Neither was the induction of RELMβ dependent on the major Th1 or Th2 cytokines. However, RELMβ stimulated naive bone marrow-derived macrophages to secrete significant amounts of TNF-α, IL-6, and RANTES. Our data suggest that RELMβ is involved in the initiation of ileitis in SAMP1/Fc mice and may act through the induction of proinflammatory cytokines from resident immune cells within the mucosa.

Mycobacterium avium paratuberculosisInvades Human Small‐Intestinal Goblet Cells and Elicits Inflammation

“…Otherwise, invasion and colonization of goblet cells by microbial pathogens has not been previously described. However, goblet cells have been demonstrated to play an important role in the pathogenesis of various animal models of inflammatory bowel disease [11,12]. The inflammation elicited by MAP infection of human goblet cells in the SCID-HU-INT model was associated with high tissue levels of IL-6, IL-1␤, and TNF-␣, which also has been reported in CD [13].…”

Proneness of TLR5 deficient mice to develop colitis is microbiota dependent

“…inherent defects in gut permeability due to overexpression of claudin-2 and reduced expression of occludin in ileal epithelial cells, and 2) overexpression of proinflammatory mediators STAT3, IL-33, and RELMb in the ileum. [9][10][11][12] Nevertheless, the microbiota still plays a role in modulating the severity of ileitis in SAMP/YitFc mice despite being dispensable in initiation of ileitis. 2 Therefore, although we demonstrate that colitis in TLR5KO mice is microbiota-dependent, caution should be exercised when extrapolating our findings to other mouse models of colitis, as each model need to be independently studied for the role of microbiota in colitis development.…”

Elevated Expression of Paneth Cell CRS4C in Ileitis-prone SAMP1/YitFc Mice

“…First, CRS4C peptide accumulation is already very high before ileitis is histologically detectable in SAMP1/YitFc mice. Second, SAMP1/YitFc mice are able to develop attenuated ileitis in the absence of intestinal microflora (69). Third, the membrane-active CRS4C peptide is highly unstable in solution and folds inefficiently in vitro.…”