Flagellin suppresses epithelial apoptosis and limits disease during enteric infection

Matam Vijay-Kumar, Huixia Wu, Rupert Jones, George Grant, Brian Babbin, Timothy P King, Denise Kelly, Andrew T Gewirtz, Andrew S Neish

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98 Citations (Scopus)

Abstract

Flagellin, the primary component of bacterial flagella, is a potent activator of toll-like receptor 5 (TLR5) signaling and is a major proinflammatory determinant of enteropathogenic Salmonella. In accordance with this, we report here that aflagellate Salmonella mutants are impaired in their ability to up-regulate proinflammatory and anti-apoptotic effector molecules in murine models of salmonellosis and that these mutants elicit markedly reduced early mucosal inflammation relative to their isogenic parent strains. Conversely, aflagellate bacteria were more potent activators of epithelial caspases and subsequent apoptosis. These phenomena correlated with a delayed but markedly exacerbated mucosal inflammation at the later stages of infection as well as elevated extra-intestinal and systemic bacterial load, culminating in a more severe clinical outcome. Systemic administration of exogenous flagellin primarily reversed the deleterious effects of in vivo Salmonella infection. These observations indicate that in Salmonella infection, flagellin plays a dominant role in activation of not only innate immunity but also anti-apoptotic processes in epithelial cells. These latter TLR-mediated responses that delay epithelial apoptosis may be as critical to mucosal defense as the classic acute inflammatory response. This notion is consistent with the emerging paradigm that specific TLR ligands may have a fundamental cytoprotective effect during inflammatory stress.
Original languageEnglish
Pages (from-to)1686-1700
Number of pages15
JournalAmerican Journal of Pathology
Volume169
Issue number5
DOIs
Publication statusPublished - 1 Nov 2006

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Keywords

  • Animals
  • Apoptosis
  • Caco-2 Cells
  • Caspases
  • Cecum
  • Cell Survival
  • Cells, Cultured
  • Disease Models, Animal
  • Enteritis
  • Epithelial Cells
  • Female
  • Flagellin
  • Humans
  • Ileum
  • Inflammation
  • Intestinal Mucosa
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Salmonella
  • Salmonella Infections

Cite this

Vijay-Kumar, M., Wu, H., Jones, R., Grant, G., Babbin, B., King, T. P., ... Neish, A. S. (2006). Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. American Journal of Pathology, 169(5), 1686-1700. https://doi.org/10.2353/ajpath.2006.060345