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Cutting edge: Crohn's disease-associated Nod2 mutation limits production of proinflammatory cytokines to protect the

Yun-Gi Kim1, Michael H Shaw, Neil Warner

  • 1Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|August 19, 2011
PubMed

Insights

Nucleotide-binding oligomerization domain 2 (Nod2) mutations linked to Crohn's disease may paradoxically protect against lethal bacterial infections. This study reveals Nod2 mutations impair bacterial recognition but reduce harmful inflammatory responses.

Area of Science:

  • Immunology
  • Genetics
  • Microbiology

Background:

  • Nucleotide-binding oligomerization domain 2 (Nod2) mutations are associated with Crohn's disease (CD).
  • CD-associated Nod2 mutations are prevalent in healthy populations, suggesting a potential protective role against other conditions.
  • Experimental evidence for this protective function is currently lacking.

Purpose of the Study:

  • To investigate the functional consequences of a specific Nod2 mutation (L1007fsinsC, equivalent to Nod2(2939iCstop)) in vivo.
  • To determine if Nod2 mutations confer protection against systemic bacterial infections.

Main Methods:

  • Utilized a mouse model expressing the Nod2(2939iCstop) mutation.
  • Assessed macrophage recognition of muramyl dipeptide and Enterococcus faecalis.
  • Measured cytokine production (TNF-α, IL-6) and lethality following E. faecalis infection.
  • Investigated the role of TNF-α signaling in E. faecalis-induced lethality.

Main Results:

  • Macrophages homozygous for Nod2(2939iCstop) exhibited impaired recognition of muramyl dipeptide and E. faecalis.
  • Nod2 deficiency and homozygocity for Nod2(2939iCstop) led to reduced TNF-α and IL-6 production.
  • Mice with Nod2 deficiency or homozygocity for Nod2(2939iCstop) showed increased lethality after systemic E. faecalis infection, despite normal bacterial loads.
  • Inhibition of TNF-α signaling protected wild-type mice from E. faecalis-induced lethality.

Conclusions:

  • The Nod2 L1007fsinsC mutation may increase susceptibility to Crohn's disease.
  • This same Nod2 mutation appears to protect against lethal systemic infection by the enteric bacterium E. faecalis.
  • The dual role of Nod2 mutations highlights a complex interplay between host genetics, inflammatory responses, and susceptibility to infectious and autoimmune diseases.

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