Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches

Abstract

Nucleotide oligomerisation domain 2 (NOD2) mutations are associated with susceptibility to Crohn's disease and graft-versus-host disease, two human disorders related with dysfunctions of Peyer's patches (PPs). In Nod2(-/-) mice transcellular permeability and bacterial translocation are increased in PPs. In this study, we show that both anti-CD4(+) and anti-interferon gamma (anti-IFNgamma) monoclonal antibodies abrogate this phenotype and reduce the expression of tumour necrosis factor (TNF) receptor 2 and the long isoform of myosin light chain kinase, thus demonstrating that immune T cells influence the epithelial functions. In turn, intraperitoneal injection of ML-7 (a myosin light chain kinase inhibitor) normalises the values of CD4(+) T cells, IFNgamma and TNFalpha. This reciprocal cross-talk is under the control of the gut microflora as shown by the normalisation of all parameters after antibiotic treatment. Toll-like receptor 2 (TLR2) and TLR4 expression were increased in Nod2(-/-) mice under basal conditions and TLR2 and TLR4 agonists induced an increased transcellular permeability in Nod2(+/+) mice. Muramyldipeptide (a Nod2 agonist) or ML-7 was able to reverse this phenomenon. It thus appears that Nod2 modulates the cross-talk between CD4(+) T cells and the epithelium recovering PP and that it downregulates the pro-inflammatory effect driven by the ileal microflora, likely by inhibiting the TLR pathways.

Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

“…Our data support the key role of TLR-2 after Y. pseudotuberculosis infection by demonstrating its role in intestinal barrier dysfunction. This finding is consistent with recent reports showing that TLR-2 activation is involved in transepithelial transport of microparticles (16,32) and transcellular permeability through PPs (42). However, the effect of TLR-2 activation on gut permeability is still subject to debate, and some studies argue for a protective role of TLR-2 on intestinal permeability.…”

“…Besides its effect on paracellular permeability, MLCK inhibition also prevents increased transcellular permeability across the FAE of PPs (27). This finding is consistent with previous studies showing that MLCK modulates the transcellular passage of antigens and microbes through PPs and that endocytosis events are increased after Y. pseudotuberculosis infection (32).…”

“…Since Y. pseudotuberculosis exhibits TLR-2 and TLR-4 agonists, and TLR-4 agonists are known to increase gut permeability (27), we also investigated the role of TLR-4. After pIB102 infection, a reduced (albeit significant) increase of paracellular permeability and E. coli translocation were observed in PPs from Tlr4 -/-mice, whereas no differences were observed at the basal level ( Figure 1, A and B).…”

Adherent-invasive E. coli in Crohn disease: bacterial “agent provocateur”

“…This seems doubtful, however, given the fact that this same immunodeficiency (if it exists) doesn't cause an increased incidence of infection with true gastrointestinal pathogens such as Shigella, an organism that also expresses LPF that would enable it to enter the Peyer's patch; and, in fact, there is no evidence that such pathogens cause CD. Another piece of evidence against this possibility is that while NOD2-deficient mice exhibit increased entry of AIEC into Peyer's patches owing to higher numbers of GP2-expressing M cells and, in general, manifest decreased epithelial barrier function, these mice do not develop colitis upon challenge with AIEC (14). This finding relates to the possibility that an underlying immunodeficiency enables AIEC-induced inflammation, because NOD2 deficiency has been associated with decreased capacity to kill intracellular organisms due to defective autophagy and that AIEC bacteria manifest enhanced proliferation in cells with a defect in autophagy due to ATG16L1 deficiency (15,16).…”

Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

“…The Th1 immune activation and increased levels of mucosal IFN-γ and TNF-α play a key role in the disruption of the epithelial barrier integrity of Peyer's patches of Nod2-deficient mice and lead to increased transcellular permeability and bacterial translocation in Peyer's patches (71).…”