Nod1 Is an Essential Signal Transducer in Intestinal Epithelial Cells Infected with Bacteria That Avoid Recognition by Toll-Like Receptors

Abstract

The transcription factor NF-κB in human intestinal epithelial cells plays a central role in regulating genes that govern the onset of mucosal inflammatory responses following intestinal microbial infection. Nod1 is a cytosolic pattern recognition receptor in mammalian cells that senses components of microbial peptidoglycans and signals the activation of NF-κB. The aim of these studies was to assess the functional importance of Nod1 in activating NF-κB and NF-κB proinflammatory target genes in human intestinal epithelium. Human colon epithelial cells that constitutively express Nod1 were used as a model intestinal epithelium. These cells do not signal through Toll-like receptor 4 (TLR4) or respond to bacterial lipopolysaccharide, but they express functional TLR5 and interleukin 1 (IL-1) receptors that signal the activation of NF-κB in response to bacterial flagellin or IL-1 stimulation. Stable expression of dominant negative (DN) Nod1 in colon epithelial cells prevented IκB kinase and NF-κB activation in response to infection with enteroinvasive Escherichia coli. In contrast, DN Nod1 did not eliminate IL-1 or flagellin-stimulated NF-κB activation. Inhibition of NF-κB was accompanied by inhibition of NF-κB target genes that provide signals for the mucosal influx of neutrophils during intestinal infection. We conclude that signaling through Nod1 is required for activating NF-κB in human intestinal epithelial cells infected with gram-negative enteric bacteria that can bypass TLR activation. Signaling through Nod1 provides the intestinal epithelium with a backup mechanism for rapidly activating innate immunity during infection with a group of highly invasive pathogenic gram-negative bacteria

TIR, CARD and PYRIN: three domains for an antimicrobial triad

“…54 Nod proteins have been shown to play a key role in host defense in response to different bacterial pathogens. Nod1 is involved in host defense towards intracellular pathogens including Shigella flexneri, 56 enteroinvasive E. coli, 57 Pseudomonas aeruginosa, 58 Chlamydiae pneumoniae, 59 as well as non invasive H. pylori which delivers muropeptides within the epithelial cells though its type IV secretion apparatus encoded by the cag pathogenicity island. 60 Nod2 is involved in the sensing of Streptococcus pneumoniae 61 and Mycobacteria.…”

Synergistic enhancement of Toll-like receptor responses by NOD1 activation

“…NOD1 mediates epithelial cell signal transduction following infection with Shigella flexneri and enteroinvasive Escherichia coli [5,6], and in vivo NOD1-deficient mice show increased susceptibility to cag pathogenicity island positive Helicobacter pylori infection [7]. Genetic variation in the NOD1 gene is associated with suscept-ibility to asthma and inflammatory bowel disease [8,9].…”

TLR Signaling in the Gut in Health and Disease

“…Nod1 and Nod2 confer responsiveness to peptidoglycan through Rip2/ RICK kinase, a mediator of NF-B activation (74 -76). Nod1 is expressed by intestinal epithelial cells and is required for recognition of invasive Gram-negative bacteria such as Shigella flexneri (77) and enteroinvasive Escherichia coli (78). The specific ligand recognized by Nod1 is found only in Gram-negative bacterial peptidoglycan.…”