Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci U S A 2010 Aug 17;107(33):14739-44
Date
08/04/2010Pubmed ID
20679225Pubmed Central ID
PMC2930434DOI
10.1073/pnas.1003363107Scopus ID
2-s2.0-77957047689 (requires institutional sign-in at Scopus site) 139 CitationsAbstract
Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2-deficient mice inoculated with Helicobacter hepaticus, an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer's patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-gamma-producing CD4 and CD8 T cells. Rip2-deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2-deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2-deficient mice by transgenic expression of alpha-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn's disease.
Author List
Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL, Kobayashi KSAuthor
Nita H. Salzman MD, PhD Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCrohn Disease
Female
Flow Cytometry
Helicobacter Infections
Helicobacter hepaticus
Host-Pathogen Interactions
Humans
Ileum
Interferon-gamma
Interleukin-1beta
Interleukin-6
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nod2 Signaling Adaptor Protein
Peyer's Patches
Reverse Transcriptase Polymerase Chain Reaction
Th1 Cells
