PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease

Zucchelli, Marco; Törkvist, Leif; Bresso, Francesca; Halfvarson, Jonas; Hellquist, Anna; Anedda, Francesca; Assadi, Ghazaleh; Lindgren, Gunnar; Svanfeldt, Monika; Janson, Martin; Noble, Colin; Pettersson, Sven; Lappalainen, Maarit; Paavola–Sakki, Paulina; Halme, Leena; Färkkilä, Martti; Turunen, Ulla; Satsangi, Jack; Kontula, Kimmo; Löfberg, Robert; Kere, Juha; D’Amato, Mauro

doi:10.1002/ibd.20963

Cited by 53 publications

(42 citation statements)

References 61 publications

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“…Recent studies have linked IBD to either polymorphisms in genes encoding SLC15 family members (35) or changes in the intestinal expression of SLC15 proteins (36). Because of the implication of NOD1 and NOD2 in IBD, we aimed to identify whether the mRNA expression levels of SLC15A4 were altered in the intestine of IBD patients.…”

Section: Resultsmentioning

confidence: 99%

pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling

Lee

Tattoli

Wojtal³

et al. 2009

Journal of Biological Chemistry

185

160

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Nod1 and Nod2 are members of the Nod-like receptor family that detect intracellular bacterial peptidoglycan-derived muramyl peptides. The biological effects of muramyl peptides have been described for over three decades, but the mechanism underlying their internalization to the cytosol remains unclear. Using the human epithelial cell line HEK293T as a model system, we demonstrate here that Nod1-activating ligands entered cells through endocytosis, most likely by the clathrin-coated pit pathway, as internalization was dynamin-dependent but not inhibited by methyl-␤-cyclodextrin. In the endocytic pathway, the cytosolic internalization of Nod1 ligands was pH-dependent, occurred prior to the acidification mediated by the vacuolar ATPase, and was optimal at pH ranging from 5.5 to 6. Similarly, the Nod2 ligand MDP was internalized into host cytosol through a similar pathway with optimal pH for internalization ranging from 5.5 to 6.5. Moreover, Nod1-activating muramyl peptides likely required processing by endosomal enzymes, prior to transport into the cytosol, suggesting the existence of a sterically gated endosomal transporter for Nod1 ligands. In support for this, we identified a role for SLC15A4, an oligopeptide transporter expressed in early endosomes, in Nod1-dependent NF-B signaling. Interestingly, SLC15A4 expression was also up-regulated in colonic biopsies from patients with inflammatory bowel disease, a disorder associated with mutations in Nod1 and Nod2. Together, our results shed light on the mechanisms by which muramyl peptides get access to the host cytosol, where they are detected by Nod1 and Nod2, and might have implications for the understanding of human diseases, such as inflammatory bowel disease.

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Section: Resultsmentioning

confidence: 99%

pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling

Lee

Tattoli

Wojtal³

et al. 2009

Journal of Biological Chemistry

185

160

View full text Add to dashboard Cite

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“…The cohort of IBD patients and ethnically matched controls from Sweden has been previously described in detail (34)(35)(36)(37). For the specific purpose of this study, 618 CD patients, 630 UC patients, and 630 blood donor controls have been included.…”

Section: Methodsmentioning

confidence: 99%

CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

Nguyen¹,

Dalmasso²,

Törkvist³

et al. 2011

J. Clin. Invest.

Self Cite

110

135

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Expression of the transmembrane glycoprotein CD98 (encoded by SLC3A2) is increased in intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), and in various carcinomas, yet its pathogenetic role remains unknown. By generating gain-and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer.

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“…Overall, our studies have revealed that PepT1 may be involved in the pathogenesis of IBD in humans. 17,49,50 However, a direct role of PepT1 in immune cells during intestinal inflammation has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis

Ayyadurai

Charania

Xiao

et al. 2013

Laboratory Investigation

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We and others have shown that the dipeptide cotransporter PepT1 is expressed in immune cells, including macrophages that are in close contact with the lamina propria of the small and large intestines. In the present study, we used PepT1-knockout (KO) mice to explore the role played by PepT1 in immune cells during dextran sodium sulfate (DSS)-induced colitis. DSS treatment caused less severe body weight loss, diminished rectal bleeding, and less diarrhea in PepT1-KO mice than in wild-type (WT) animals. A histological examination of colonic sections revealed that the colonic architecture was less disrupted and the extent of immune cell infiltration into the mucosa and submucosa following DSS treatment was reduced in PepT1-KO mice compared with WT animals. Consistent with these results, the DSS-induced colitis increase in colonic myeloperoxidase activity was significantly less in PepT1-KO mice than in WT littermates. The colonic levels of mRNAs encoding the inflammatory cytokines CXCL1, interleukin (IL)-6, monocyte chemotactic protein-1, IL-12, and interferon-g were significantly lower in DSS-treated PepT1-KO mice than in DSS-treated WT animals. Colonic immune cells from WT had significantly higher level of proinflammatory cytokines then PepT1 KO. In addition, we observed that knocking down the PepT1 expression decreases chemotaxis of immune cells recruited during intestinal inflammation. Antibiotic treatment before DSS-induced colitis eliminated the differential expression of inflammatory cytokines between WT and PepT1-KO mice. In conclusion, PepT1 in immune cells regulates the secretion of proinflammatory cytokines triggered by bacteria and/or bacterial products, and thus has an important role in the induction of colitis. PepT1 may transport small bacterial products, such as muramyl dipeptide and the tripeptide L-Ala-gamma-D-Glu-meso-DAP, into macrophages. These materials may be sensed by members of the nucleotide-binding site-leucine-rich repeat family of intracellular receptors, ultimately resulting in altered homeostasis of the intestinal microbiota.

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PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease

Abstract: A functional polymorphism in the SLC15A1 gene might be of relevance to inflammation and antibacterial responses in IBD. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations.

Cited by 53 publications

References 61 publications

pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling

pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling

CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis

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