TY - JOUR
T1 - The Nod2 Sensor Promotes Intestinal Pathogen Eradication via the Chemokine CCL2-Dependent Recruitment of Inflammatory Monocytes
AU - Kim, Yun Gi
AU - Kamada, Nobuhiko
AU - Shaw, Michael H.
AU - Warner, Neil
AU - Chen, Grace Y.
AU - Franchi, Luigi
AU - Núñez, Gabriel
N1 - Funding Information:
We thank R. Flavell, T. Mak, and K. Pienta for generous supply of mutant mice and D. Schauer for bacterial strains. S. Koonse for excellent animal husbandry, and J. Whitfield for ELISA assays. This work was supported by NIH grant R01 DK61707 and funds to the Michigan Comprehensive Cancer Center Immunology Monitoring Core from the University of Michigan's Cancer Center Support Grant (5 P30 CA46592). Y.-G. Kim was supported by training funds from the University of Michigan Comprehensive Cancer Center, N.K. by a Fellowship from the Uehara Memorial Foundation, L.F. by a Career Development Award from the Crohn's and Colitis Foundation of America, and M.H.S. by training grant 2T32 HL007517 from the NIH.
PY - 2011/5/27
Y1 - 2011/5/27
N2 - The intracellular sensor Nod2 is activated in response to bacteria, and the impairment of this response is linked to Crohn's disease. However, the function of Nod2 in host defense remains poorly understood. We found that Nod2-/- mice exhibited impaired intestinal clearance of Citrobacter rodentium, an enteric bacterium that models human infection by pathogenic Escherichia coli. The increased bacterial burden was preceded by reduced CCL2 chemokine production, inflammatory monocyte recruitment, and Th1 cell responses in the intestine. Colonic stromal cells, but not epithelial cells or resident CD11b+ phagocytic cells, produced CCL2 in response to C. rodentium in a Nod2-dependent manner. Unlike resident phagocytic cells, inflammatory monocytes produced IL-12, a cytokine that induces adaptive immunity required for pathogen clearance. Adoptive transfer of Ly6Chi monocytes restored the clearance of the pathogen in infected Ccr2-/- mice. Thus, Nod2 mediates CCL2-CCR2-dependent recruitment of inflammatory monocytes, which is important in promoting bacterial eradication in the intestine.
AB - The intracellular sensor Nod2 is activated in response to bacteria, and the impairment of this response is linked to Crohn's disease. However, the function of Nod2 in host defense remains poorly understood. We found that Nod2-/- mice exhibited impaired intestinal clearance of Citrobacter rodentium, an enteric bacterium that models human infection by pathogenic Escherichia coli. The increased bacterial burden was preceded by reduced CCL2 chemokine production, inflammatory monocyte recruitment, and Th1 cell responses in the intestine. Colonic stromal cells, but not epithelial cells or resident CD11b+ phagocytic cells, produced CCL2 in response to C. rodentium in a Nod2-dependent manner. Unlike resident phagocytic cells, inflammatory monocytes produced IL-12, a cytokine that induces adaptive immunity required for pathogen clearance. Adoptive transfer of Ly6Chi monocytes restored the clearance of the pathogen in infected Ccr2-/- mice. Thus, Nod2 mediates CCL2-CCR2-dependent recruitment of inflammatory monocytes, which is important in promoting bacterial eradication in the intestine.
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U2 - 10.1016/j.immuni.2011.04.013
DO - 10.1016/j.immuni.2011.04.013
M3 - Article
C2 - 21565531
AN - SCOPUS:79956319462
SN - 1074-7613
VL - 34
SP - 769
EP - 780
JO - Immunity
JF - Immunity
IS - 5
ER -