Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer

被引:252
作者
Hu, Bo [1 ,2 ]
Elinav, Eran [1 ,7 ]
Huber, Samuel [1 ,8 ]
Strowig, Till [1 ]
Hao, Liming [3 ]
Hafemann, Anja [1 ]
Jin, Chengcheng [1 ,4 ]
Eisenbarth, Stephanie C. [5 ]
Flavell, Richard A. [1 ,6 ]
机构
[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06520 USA
[5] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA
[6] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[7] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel
[8] Univ Hosp Hamburg Eppendor, Dept Med 1, D-20246 Hamburg, Germany
基金
美国国家卫生研究院;
关键词
colon cancer; microflora; ASC; COLORECTAL-CANCER; INTESTINAL INFLAMMATION; ULCERATIVE-COLITIS; COLON INFLAMMATION; TUMORIGENESIS; PROGRESSION; CASPASE-1; RISK; CARCINOGENESIS; MICROFLORA;
D O I
10.1073/pnas.1307575110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The microbiota is pivotal in the pathogenesis of inflammatory bowel disease (IBD)-associated inflammation-induced colorectal cancer (CRC), yet mechanisms for these effects remain poorly characterized. Here, we demonstrate that aberrant inflammasome-induced microbiota plays a critical role in CRC development, where mice deficient in the NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome feature enhanced inflammation-induced CRC formation. Intriguingly, WT mice cohoused either with inflammasome-deficient mice or with mice lacking IL-18 feature exacerbated inflammation-induced CRC compared with singly housed WT mice. Enhanced tumorigenesis is dependent on microbiota-induced chemokine (C-C motif) ligand 5 (CCL5)-driven inflammation, which in turn promotes epithelial cell proliferation through local activation of the IL-6 pathway, leading to cancer formation. Altogether, our results mechanistically link the altered microbiota with the pathogenesis of inflammation-induced CRC and suggest that in some conditions, microbiota components may transfer CRC susceptibility between individuals.
引用
收藏
页码:9862 / 9867
页数:6
相关论文
共 47 条
[1]   The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role [J].
Abdulamir, Ahmed S. ;
Hafidh, Rand R. ;
Abu Bakar, Fatimah .
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2011, 30
[2]   NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling [J].
Allen, Irving C. ;
Wilson, Justin E. ;
Schneider, Monika ;
Lich, John D. ;
Roberts, Reid A. ;
Arthur, Janelle C. ;
Woodford, Rita-Marie T. ;
Davis, Beckley K. ;
Uronis, Joshua M. ;
Herfarth, Hans H. ;
Jobin, Christian ;
Rogers, Arlin B. ;
Ting, Jenny P. -Y. .
IMMUNITY, 2012, 36 (05) :742-754
[3]   The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer [J].
Allen, Irving C. ;
TeKippe, Erin McElvania ;
Woodford, Rita-Marie T. ;
Uronis, Joshua M. ;
Holl, Eda K. ;
Rogers, Arlin B. ;
Herfarth, Hans H. ;
Jobin, Christian ;
Ting, Jenny P. -Y. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (05) :1045-1056
[4]   Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota [J].
Arthur, Janelle C. ;
Perez-Chanona, Ernesto ;
Muehlbauer, Marcus ;
Tomkovich, Sarah ;
Uronis, Joshua M. ;
Fan, Ting-Jia ;
Campbell, Barry J. ;
Abujamel, Turki ;
Dogan, Belgin ;
Rogers, Arlin B. ;
Rhodes, Jonathan M. ;
Stintzi, Alain ;
Simpson, Kenneth W. ;
Hansen, Jonathan J. ;
Keku, Temitope O. ;
Fodor, Anthony A. ;
Jobin, Christian .
SCIENCE, 2012, 338 (6103) :120-123
[5]   Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome [J].
Bauer, Christian ;
Duewell, Peter ;
Mayer, Christine ;
Lehr, Hans Anton ;
Fitzgerald, Katherine A. ;
Dauer, Marc ;
Tschopp, Jurg ;
Endres, Stefan ;
Latz, Eicke ;
Schnurr, Max .
GUT, 2010, 59 (09) :1192-1199
[6]   TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].
Becker, C ;
Fantini, MC ;
Schramm, C ;
Lehr, HA ;
Wirtz, S ;
Nikolaev, A ;
Burg, J ;
Strand, S ;
Kiesslich, R ;
Huber, S ;
Ito, H ;
Nishimoto, N ;
Yoshizaki, K ;
Nishimoto, N ;
Galle, PR ;
Blessing, M ;
Rose-John, S ;
Neurath, MF .
IMMUNITY, 2004, 21 (04) :491-501
[7]   High resolution colonoscopy in live mice [J].
Becker, C. ;
Fantini, M. C. ;
Neurath, M. F. .
NATURE PROTOCOLS, 2006, 1 (06) :2900-2904
[8]   gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis [J].
Bollrath, Julia ;
Phesse, Toby J. ;
von Burstin, Vivian A. ;
Putoczki, Tracy ;
Bennecke, Moritz ;
Bateman, Trudie ;
Nebelsiek, Tim ;
Lundgren-May, Therese ;
Canli, Oezge ;
Schwitalla, Sarah ;
Matthews, Vance ;
Schmid, Roland M. ;
Kirchner, Thomas ;
Arkan, Melek C. ;
Ernst, Matthias ;
Greten, Florian R. .
CANCER CELL, 2009, 15 (02) :91-102
[9]   A Functional Role for Nlrp6 in Intestinal Inflammation and Tumorigenesis [J].
Chen, Grace Y. ;
Liu, Maochang ;
Wang, Fuyuan ;
Bertin, John ;
Nunez, Gabriel .
JOURNAL OF IMMUNOLOGY, 2011, 186 (12) :7187-7194
[10]   Gastrointestinal microflora, food components and colon cancer prevention [J].
Davis, Cindy D. ;
Milner, Jofm A. .
JOURNAL OF NUTRITIONAL BIOCHEMISTRY, 2009, 20 (10) :743-752