Intestinal Epithelial Cell Up-Regulation of LY6 Molecules during Colitis Results in Enhanced Chemokine Secretion

Flanagan, Ken; Modrušan, Zora; Cornelius, Jennine; Chavali, Arvind K.; Kasman, Ian; Kömüves, László G.; Mo, Lian; Diehl, Lauri

doi:10.4049/jimmunol.180.6.3874

Cited by 34 publications

(32 citation statements)

References 57 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). In addition, infiltration of CD11c + cells together with proinflammatory Ly-6C hi monocytes were a sign of pronounced colonic inflammation, as previously observed in patients with IBD (17). Differences in leukocyte infiltration between Il10 −/− (33%) and S3/I10 −/− mice (22%) persisted at 14 wk of age ( Fig.…”

Section: Significancesupporting

confidence: 61%

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Kurakevich

Hennet

Hausmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Breast milk oligosaccharides shape the intestinal environment by affecting mucosal immunity and bacterial colonization. To clarify the role of milk oligosaccharide sialyl(α2,3)lactose (3SL) in intestinal physiology and disease, we investigated colitis development in Il10 −/− mice exposed to normal or 3SL-deficient milk during lactation. Onset and progression of intestinal inflammation were delayed in Il10 −/− mice deficient for the α2,3 sialyltransferase 4 (ST3GAL4) responsible for 3SL biosynthesis. The proinflammatory role of 3SL was confirmed by showing that oral supplementation of newborn Il10 −/− ;St3gal4 −/− mice with 3SL increased colitis severity. Conversely, fostering of newborn Il10 −/− mice to lactating St3gal4 −/− mothers reduced colitis severity. 3SL directly stimulated mesenteric lymph node CD11c + dendritic cells and induced production of cytokines required for expansion of T H 1 and T H 17 T cells. The stimulatory effect of 3SL was attenuated in Tlr4-deficient CD11c + cells, demonstrating that 3SL induces inflammation through Toll-like receptor 4 (TLR4) signaling. Thus, 3SL directly modulates mucosal immunity, which increases susceptibility to colitis.carbohydrate | glycan | prebiotics | mouse innate immunity I nflammatory bowel disease (IBD) affects up to 0.8% of the Western population and this number is constantly growing worldwide (1). The etiology of IBD is not fully understood, although a number of genetic and environmental factors leading to aberrant mucosal immune responses have been identified (2). Nutrition and especially breastfeeding affects the risk for IBD (3). Breastfeeding for at least 3 mo, accordingly, contributes to a lower incidence for IBD (4); however, these data still are controversial. Oligosaccharides are major constituents of breast milk fulfilling various functions, such as promoting growth of beneficial bacteria, acting as soluble receptors preventing attachment of pathogens in the gastrointestinal tract, and reducing adhesion of leukocytes (4, 5). The exact functions of individual oligosaccharides remain however largely unknown.The limited structural diversity of mouse milk oligosaccharides, including only sialyl(α2,3)lactose (3SL) and sialyl(α2,6)lactose (6SL), enables assessing the specific functional contribution of these oligosaccharides to intestinal homeostasis (6). A recent study provided unique evidence that milk-derived 3SL, but not 6SL, increased susceptibility to dextran sulfate sodium (DSS)-induced acute colitis (6). These findings indicate that individual milk oligosaccharides may not only mediate protective effects, but may promote inflammation as well.Mucosal innate immunity has a pivotal role in regulating inflammatory responses (2). Dendritic cells (DCs) and macrophages sense luminal antigens and provide signals for induction of tolerance to ingested antigens and commensal bacteria or for initiation of inflammatory immune responses, facilitating activation of adaptive immunity (7,8). Intestinal DCs consist of two functionally distinct subsets based on e...

show abstract

Section: Significancesupporting

confidence: 61%

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Kurakevich

Hennet

Hausmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The simplest explanation is that IFN-␥ activates macrophages and neutrophils for E. histolytica killing, which has been shown in vitro (13,36). Alternately, it is possible that IFN-␥ exerts protective effects (e.g., inducing production of chemokines [15,18] and mucosal defense molecules [16]) on the epithelium, which bone marrow chimera experiments indicate is a critical cell type in the mouse strain-specific resistance to intestinal E. histolytica infection (23).…”

Section: Discussionmentioning

confidence: 99%

Protection against Intestinal Amebiasis by a Recombinant Vaccine Is Transferable by T Cells and Mediated by Gamma Interferon

et al. 2009

View full text Add to dashboard Cite

We have previously shown that vaccination with purified Entamoeba histolytica Gal/GalNAc lectin or recombinant subunits can protect mice from intestinal amebiasis upon intracecal challenge. In this study, we demonstrated with adoptive-transfer experiments that this lectin vaccine protection is mediated by T cells but not serum. The cell-mediated immune (CMI) response was characterized by significant gamma interferon (IFN-␥), interleukin 12 (IL-12), IL-2, IL-10, and IL-17 production. To move toward a human vaccine, we switched to a recombinant protein and tested a range of adjuvants and routes appropriate for humans. We found that subcutaneous delivery of LecA with IDRI's adjuvant system EM014 elicited a potent Th1-type CMI profile and provided significant protection, as measured by culture negativity (79% efficacy); intranasal immunization with cholera toxin provided 56% efficacy; and alum induced a Th2-type response that protected 62 to 68% of mice. Several antibody and CMI cytokine responses were examined for correlates of protection, and prechallenge IFN-␥ ؉ or IFN-␥-, IL-2-, and tumor necrosis factor alpha-triple-positive CD4 cells in blood were statistically associated with protection. To test the role of IFN-␥ in LecA-mediated protection, we neutralized IFN-␥ in LecA-immunized mice and found that it abrogated the protection conferred by vaccination. These data demonstrate that CMI is sufficient for vaccine protection from intestinal amebiasis and reveal an important role for IFN-␥, even in the setting of alum.The enteric protozoan parasite Entamoeba histolytica is the causative pathogen of amebic dysentery and liver abscess that affects millions of people worldwide. Bangladeshi children experience a 40% annual incidence of E. histolytica infection (24), and evidence of prior E. histolytica infection can be detected in 8.4% of the general population in Mexico (6). Despite the availability of effective antibiotics, the World Health Organization estimates that up to 100,000 deaths occur annually, highlighting the need for alternate approaches to control amebiasis. One approach is to develop a vaccine to prevent intestinal infection (26).Several vaccine candidates for amebiasis have been proposed (48), including the serine-rich E. histolytica protein, peroxiredoxin, the EhCP112 molecule, and the galactose/N-acetyl-Dgalactosamine-inhibitable lectin (Gal/GalNAc lectin). A significant body of work has focused on the latter: vaccination with either parasite-purified Gal/GalNAc lectin (10,29,32,38,40) or recombinant lectin subunits has provided protection in rodent models against amebic liver abscess and amebic colitis (29,37,46,47,53). Although these results are encouraging, two limitations remain. First, in most of these vaccine studies, the adjuvants and delivery routes are not compatible with eventual use in humans. Second, the mechanisms of amebiasis vaccine-mediated protection are still not fully understood. For instance, in the intestinal model, there was an association between the presence of an antiparasit...

show abstract

“…Those authors identified the LY6A gene superfamily as strongly upregulated in inflamed intestinal epithelial cells. The majority of LY6 family members are GPI-anchored cell surface glycoproteins with broad distribution on cells of hematopoietic origin (32). Surface expression of LY6A was induced by IL-22 and interferon (IFN)-␥ and resulted in production of a number of chemokines known to be involved in the immunopathogenesis of IBD.…”

Section: Epithelial Barriermentioning

confidence: 99%

Bacterial-mucosal interactions in inflammatory bowel disease—an alliance gone bad

Chichlowski

Hale²

2008

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

The complex interaction of genetic, microbial, and environmental factors may result in continuous activation of the mucosal immune system leading to inflammatory bowel disease (IBD). Most present treatments for IBD involve altering or suppressing the aberrant immune response; however, the role of the intestinal microbiota in the pathophysiology of IBD is becoming more evident. The epithelial layer is essential for the proper functioning of the gastrointestinal tract, and its increased permeability to the luminal antigens may lead to the inflammatory processes and mucosal damage observed in IBD. Factors affecting the efficacy of the epithelial barrier include presence of pathogenic bacteria (e.g., Helicobacter spp.), presence of probiotic bacteria, availability of selected nutrients, and others. Defective function of the mucosal barrier might facilitate the contact of bacterial antigens and adjuvants with innate and adaptive immune cells to generate prolonged inflammatory responses. This review will briefly describe the complex structure of the epithelial barrier in the context of bacterial-mucosal interactions observed in human IBD and mouse models of colitis.

show abstract

Intestinal Epithelial Cell Up-Regulation of LY6 Molecules during Colitis Results in Enhanced Chemokine Secretion

Cited by 34 publications

References 57 publications

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Protection against Intestinal Amebiasis by a Recombinant Vaccine Is Transferable by T Cells and Mediated by Gamma Interferon

Bacterial-mucosal interactions in inflammatory bowel disease—an alliance gone bad

Contact Info

Product

Resources

About

Intestinal Epithelial Cell Up-Regulation of LY6 Molecules during Colitis Results in Enhanced Chemokine Secretion

Cited by 34 publications

References 57 publications

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c + cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c + cells through TLR4

Protection against Intestinal Amebiasis by a Recombinant Vaccine Is Transferable by T Cells and Mediated by Gamma Interferon

Bacterial-mucosal interactions in inflammatory bowel disease—an alliance gone bad

Contact Info

Product

Resources

About

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4