4th Annual BMRP Investigator Meeting - Abstract

Role of Nod2 in the control of Paneth cell function and intestinal microflora

Mathilde Body-Malapel^a, Mathias Chamaillard, Thirumala Devi-Kanneganti, Amal Amer and Gabriel Nuñez^b

Department of Pathology, University of Michigan Medical School (Ann Arbor, Michigan, U.S.A.)

NOD2 is an intracellular protein that recognizes muramyl dipeptide (MDP), a conserved motif in bacterial peptidoglycan, and activates a host immune response against bacteria.  Genetic variation in the NOD2 protein resulting in defective responses to MDP is associated with susceptibility to Crohn’s disease (CD).  NOD2 is expressed in bone marrow derived monocyte/dendritic cells and in Paneth cells, a specialized type of epithelial cell located in the crypts of the small intestine that secrete anti-microbial peptides in response to bacterial components including MDP.  Stimulation of NOD2 with MDP synergizes with Toll-like receptor ligands for the induction of inflammatory cytokines in macrophages.  This is abolished in macrophages deficient in Nod2 and Nod2 knockout (KO) mice primed with MDP prior to LPS stimulation.  Secretion of IL-1β, IL-6, and TNF-α as well as the activation of caspase-1 in response to Listeria monocytogenes or Salmonella were not affected in bone-marrow derived macrophages from Nod2 KO when compared to macrophages from wild-type mice.  However, Nod2 KO mice are more susceptible to oral inoculation, but not intraperitoneal or intravenous infection, with L. monocytogenes than wild-type mice, a finding that is correlated with reduced expression of some cryptdins in the terminal ileum of Nod2 KO mice.  The impairment of NOD2 function associated with CD-associated NOD2 mutations may lead to defective elimination of certain intestinal bacteria in the ileal crypts and this defect might be important in eliciting an abnormal inflammatory response in the underlying intestinal tissue.

^aCo-Investigator and Presenter; ^bPrincipal Investigator