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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 γ (anti-IFNγ) 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, IFNγ and TNFα. 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.

  • Nod2
  • Peyer's patch
  • MLCK
  • epithelial permeability
  • gut microflora
  • Crohn's disease
  • graft-versus-host disease
  • IBD
  • IBD basic research
  • immune response
  • CARD15
  • caspase recruitment domain 15
  • CD
  • Crohn's disease
  • DC
  • dendritic cell
  • FAE
  • follicle-associated epithelium
  • GALT
  • gut-associated lymphoid tissue
  • GVHD
  • graft-versus-host disease
  • LFs
  • lymphoid follicles
  • LPS
  • lipopolysaccharide
  • MDP
  • muramyl dipeptide
  • MLCK
  • myosin light chain kinase
  • NLRC2
  • natch Leucine-rich-repeat Card 2
  • NOD2
  • nucleotide oligomerisation domain 2
  • PGN
  • peptigoglycan
  • PP
  • Peyer's patches
  • Th1/2
  • T helper type 1/2
  • TLR
  • toll-like receptor
  • TNFR
  • TNF receptor
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