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

Abstract

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.

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

“…These results suggest that bacteria and/or bacterial products play an important role in the exacerbation of DSS-induced colitis in mice and further suggest that miR-193a-3p is crucial for regulating PepT1-mediated bacterial products in inducing intestinal inflammation. These data are consistent with a recent work demonstrating that knocking down the PepT1 expression decreases chemotaxis of immune cells recruited during intestinal inflammation, which is dependent on bacteria and/or bacterial products (34). miRNAs can modulate cellular activities through the regulation of extensive gene networks and may exert different functions that depend on the cellular context (41).…”

A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-cis-12-octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40-MEK-ERK Pathway

“…TNFR2 signaling mediates the activation of MLCK and the change in localization of occludin. TNFR2 signaling also induces infiltration of macrophages and neutrophils into the lamina propria and activates Th17 cells (50,51). Su et al (20) reported that the induced expression of TNFR2 in murine colitis promoted apoptosis of intestinal epithelial cells, chemokine overexpression, and exacerbation of inflammation.…”

Colonic miRNA Expression/Secretion, Regulated by Intestinal Epithelial PepT1, Plays an Important Role in Cell-to-Cell Communication during Colitis

“…Colitis was induced by the addition of 3% (w/v) dextran sodium sulfate (DSS; molecular weight 36,000–50,000 Da; MP Biomedicals, LLC, OH) to the drinking water [9]. Physical characteristics such as body weight and pro and anti-inflammatory cytokine profile were matched with previously reported [10].…”

“…Recently, a polymorphism of the hPepT1 gene has been shown to be associated with IBD susceptibility, indicating a direct involvement of this transporter in IBD [8]. Also, it has been shown that PepT1 expressed in immune cells played an important role in promoting the immune response during experimentally induced colitis compared to the knock-out mice [9]. Recent study showed that IL-16 induces intestinal inflammation by up regulating PepT1 expression in puffer fish intestine and it subsequently transported the bacterial peptide fMLP which triggers the intestinal inflammation [7].…”