TY - JOUR
T1 - NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis
AU - Elinav, Eran
AU - Strowig, Till
AU - Kau, Andrew L.
AU - Henao-Mejia, Jorge
AU - Thaiss, Christoph A.
AU - Booth, Carmen J.
AU - Peaper, David R.
AU - Bertin, John
AU - Eisenbarth, Stephanie C.
AU - Gordon, Jeffrey I.
AU - Flavell, Richard A.
N1 - Funding Information:
We would like to thank A Hafemann, S. Campton, E. Eynon, J. Alderman, W. Philbrick, C. Zorca, M. Musaheb, J. Stein, A. Ferrandino, F. Manzo, and the members of the Flavell lab for technical help and helpful discussions;K. Fitzgerald for providing AIM2 −/− deficient mice; M. Graham and C. Rahner, CCMI EM Core Facility, Yale School of Medicine; J. Manchester and S. Deng for their assistance with DNA sequencing; V. Nagy for discussion and help with figure preparation; and H. Elinav for important discussions, suggestions, and critique. E.E. is supported by Cancer Research Institute (2010-2012) and the Israel-US educational foundation (2009) and is the recipient of the Claire and Emmanuel G. Rosenblatt award from the American Physicians for Medicine in Israel Foundation. A.L.K. is the recipient of a postdoctoral fellowship from the W.M Keck Foundation. J.H.-M. is supported by a LLS Postdoctoral Fellowship. This work was supported, in part, by Howard Hughes Medical Institute (R.A.F.) and the Crohn's and Colitis Foundation of America (J.I.G.).
PY - 2011/5/27
Y1 - 2011/5/27
N2 - Inflammasomes are multiprotein complexes that function as sensors of endogenous or exogenous damage-associated molecular patterns. Here, we show that deficiency of NLRP6 in mouse colonic epithelial cells results in reduced IL-18 levels and altered fecal microbiota characterized by expanded representation of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7. NLRP6 inflammasome-deficient mice were characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, and exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS). Cross-fostering and cohousing experiments revealed that the colitogenic activity of this microbiota is transferable to neonatal or adult wild-type mice, leading to exacerbation of DSS colitis via induction of the cytokine, CCL5. Antibiotic treatment and electron microscopy studies further supported the role of Prevotellaceae as a key representative of this microbiota-associated phenotype. Altogether, perturbations in this inflammasome pathway, including NLRP6, ASC, caspase-1, and IL-18, may constitute a predisposing or initiating event in some cases of human IBD. PaperClip:
AB - Inflammasomes are multiprotein complexes that function as sensors of endogenous or exogenous damage-associated molecular patterns. Here, we show that deficiency of NLRP6 in mouse colonic epithelial cells results in reduced IL-18 levels and altered fecal microbiota characterized by expanded representation of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7. NLRP6 inflammasome-deficient mice were characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, and exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS). Cross-fostering and cohousing experiments revealed that the colitogenic activity of this microbiota is transferable to neonatal or adult wild-type mice, leading to exacerbation of DSS colitis via induction of the cytokine, CCL5. Antibiotic treatment and electron microscopy studies further supported the role of Prevotellaceae as a key representative of this microbiota-associated phenotype. Altogether, perturbations in this inflammasome pathway, including NLRP6, ASC, caspase-1, and IL-18, may constitute a predisposing or initiating event in some cases of human IBD. PaperClip:
UR - http://www.scopus.com/inward/record.url?scp=79957576718&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.04.022
DO - 10.1016/j.cell.2011.04.022
M3 - Article
C2 - 21565393
AN - SCOPUS:79957576718
SN - 0092-8674
VL - 145
SP - 745
EP - 757
JO - Cell
JF - Cell
IS - 5
ER -