Cutting Edge: Crohn's disease-associated Nod2 mutation limits production of proinflammatory cytokines to protect the host from Enterococcus faecalis-induced lethality

Yun Gi Kim, Michael H. Shaw, Neil Warner, Jong Hwan Park, Felicia Chen, Yasunori Ogura, Gabriel Núñez

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Nucleotide-binding oligomerization domain 2 (Nod2) mutations including L1007fsinsC are associated with the development of Crohn's disease (CD). These CD-associated Nod2 mutations are common in healthy white populations, suggesting that they may confer some protective function, but experimental evidence is lacking. Using a mouse strain that expresses Nod22939iCstop, the equivalent of the L1007fsinsC mutation, we found that macrophages homozygous for Nod22939iCstop are impaired in the recognition of muramyl dipeptide and Enterococcus faecalis, a commensal bacterium that is a common cause of sepsis-associated lethality in humans. Notably, Nod2 deficiency and homozygocity for Nod22939iCstop were associated with reduced production of TNF-α and IL-6 and lethality after systemic infection with E. faecalis despite normal bacteria loads. Consistently, inhibition of TNF-α signaling protected wild-type mice from E. faecalis-induced lethality. These results suggest that the same Nod2 mutation can increase the susceptibility to CD, but also protect the host from systemic infection by a common enteric bacterium.

Original languageEnglish
Pages (from-to)2849-2852
Number of pages4
JournalJournal of Immunology
Volume187
Issue number6
DOIs
Publication statusPublished - 2011 Sep 15

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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