TY - JOUR
T1 - Dysregulated NOD2 predisposes SAMP1/YitFc mice to chronic intestinal inflammation
AU - Corridoni, Daniele
AU - Kodani, Tomohiro
AU - Rodriguez-Palacios, Alexander
AU - Pizarro, Theresa T.
AU - Xin, Wei
AU - Nickerson, Kourtney P.
AU - McDonald, Christine
AU - Ley, Klaus F.
AU - Abbott, Derek W.
AU - Cominelli, Fabio
PY - 2013/10/15
Y1 - 2013/10/15
N2 - Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn's disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.
AB - Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn's disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.
UR - http://www.scopus.com/inward/record.url?scp=84885698235&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885698235&partnerID=8YFLogxK
U2 - 10.1073/pnas.1311657110
DO - 10.1073/pnas.1311657110
M3 - Article
C2 - 24082103
AN - SCOPUS:84885698235
SN - 0027-8424
VL - 110
SP - 16999
EP - 17004
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -