Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches.
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.
Barreau
Frédérick
F
INSERM, U843, Paris, France.
Madre
Chrystèle
C
Meinzer
Ulrich
U
Berrebi
Dominique
D
Dussaillant
Monique
M
Merlin
Françoise
F
Eckmann
Lars
L
Karin
Mickael
M
Sterkers
Ghislaine
G
Bonacorsi
Stéphane
S
Lesuffleur
Thécla
T
Hugot
Jean-Pierre
JP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018988:Bacterial Translocation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015194:Diffusion Chambers, Culture; D007082:Ileum / Q000382:microbiology; D007371:Interferon-gamma / Q000276:immunology; D007408:Intestinal Absorption / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D010539:Permeability; D010581:Peyer's Patches / Q000276:immunology* / Q000382:microbiology* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology
D000900:Anti-Bacterial Agents; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma