Abstract
SUMMARYInflammatory bowel disease (IBD), in the form of Crohn’s disease (CD) or ulcerative colitis (UC), is a debilitating chronic immune disorder of the intestine. A complex etiology resulting from dysfunctional interactions between the intestinal immune system and its microflora, influenced by host genetic susceptibility, makes disease modeling challenging. Mutations in NOD2 have the highest disease-specific risk association for CD, and a related gene, NOD1, is associated with UC. NOD1 and NOD2 encode intracellular bacterial sensor proteins acting as innate immune triggers, and represent promising therapeutic targets. The zebrafish has the potential to aid in modeling genetic and environmental aspects of IBD pathogenesis. Here, we report the characterization of the Nod signaling components in the zebrafish larval intestine. The nod1 and nod2 genes are expressed in intestinal epithelial cells and neutrophils together with the Nod signaling pathway genes ripk2, a20, aamp, cd147, centaurin b1, erbin and grim-19. Using a zebrafish embryo Salmonella infection model, morpholino-mediated depletion of Nod1 or Nod2 reduced the ability of embryos to control systemic infection. Depletion of Nod1 or Nod2 decreased expression of dual oxidase in the intestinal epithelium and impaired the ability of larvae to reduce intracellular bacterial burden. This work highlights the potential use of zebrafish larvae in the study of components of IBD pathogenesis.
Highlights
The mammalian NOD genes encode proteins that have been implicated in the pathogenesis of immune-mediated diseases, including inflammatory bowel disease (IBD), graft-versus-host disease and uveitis (Hugot et al, 2001; Ogura et al, 2001; Rosenbaum et al, 2003; Holler et al, 2004; Brenmoehl et al, 2007)
NOD2 was the first gene linked to IBD (Hugot et al, 2001; Ogura et al, 2001) and is the locus most strongly linked to the disorder
Sequences encoding a20, centaurin b1, erbin and grim-19 were isolated by reverse-transcriptase PCR (RT-PCR) from larval cDNA
Summary
The mammalian NOD genes encode proteins that have been implicated in the pathogenesis of immune-mediated diseases, including inflammatory bowel disease (IBD), graft-versus-host disease and uveitis (Hugot et al, 2001; Ogura et al, 2001; Rosenbaum et al, 2003; Holler et al, 2004; Brenmoehl et al, 2007). Genetic susceptibility loci for the major forms of IBD (Crohn’s disease and ulcerative colitis) include components of the innate immune system (Mathew, 2008). Our laboratory has analyzed the zebrafish NOD orthologs to explore the use of this model in understanding aspects of IBD genetics
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