Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis

被引:998
作者
Lee, Yun Kyung [1 ]
Menezes, Juscilene S. [1 ]
Umesaki, Yoshinori [2 ]
Mazmanian, Sarkis K. [1 ]
机构
[1] CALTECH, Div Biol, Pasadena, CA 91125 USA
[2] Yakult Cent Inst Microbiol Res, Tokyo 1868650, Japan
关键词
Th17; cells; Foxp(3+) regulatory T cells; autoimmunity; multiple sclerosis; segmented filamentous bacteria; SEGMENTED FILAMENTOUS BACTERIA; MULTIPLE-SCLEROSIS; MOLECULAR ANALYSIS; LAMINA PROPRIA; MOUSE MODEL; DIFFERENTIATION; SUSCEPTIBILITY; MINOCYCLINE; MECHANISMS; MATURATION;
D O I
10.1073/pnas.1000082107
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
Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-gamma and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp(3+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro-and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.
引用
收藏
页码:4615 / 4622
页数:8
相关论文
共 47 条
[31]   Regulatory T cells and immune tolerance [J].
Sakaguchi, Shimon ;
Yamaguchi, Tomoyuki ;
Nomura, Takashi ;
Ono, Masahiro .
CELL, 2008, 133 (05) :775-787
[32]   Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease [J].
Sakaguchi, Shimon ;
Ono, Masahiro ;
Setoguchi, Ruka ;
Yagi, Haruhiko ;
Hori, Shohei ;
Fehervari, Zoltan ;
Shimizu, Jun ;
Takahashi, Takeshi ;
Nomura, Takashi .
IMMUNOLOGICAL REVIEWS, 2006, 212 :8-27
[33]  
Sartor RB, 2005, CURR OPIN GASTROEN, V21, P44
[35]   Multiple sclerosis:: an infectious syndrome involving Chlamydophila pneumoniae [J].
Stratton, Charles W. ;
Wheldon, David B. .
TRENDS IN MICROBIOLOGY, 2006, 14 (11) :474-479
[36]   Active induction of experimental allergic encephalomyelitis [J].
Stromnes, Ingunn M. ;
Goverman, Joan M. .
NATURE PROTOCOLS, 2006, 1 (04) :1810-1819
[37]  
Talham GL, 1999, INFECT IMMUN, V67, P1992
[38]   Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis [J].
Thacker, EL ;
Mirzaei, F ;
Ascherio, A .
ANNALS OF NEUROLOGY, 2006, 59 (03) :499-503
[39]   A core gut microbiome in obese and lean twins [J].
Turnbaugh, Peter J. ;
Hamady, Micah ;
Yatsunenko, Tanya ;
Cantarel, Brandi L. ;
Duncan, Alexis ;
Ley, Ruth E. ;
Sogin, Mitchell L. ;
Jones, William J. ;
Roe, Bruce A. ;
Affourtit, Jason P. ;
Egholm, Michael ;
Henrissat, Bernard ;
Heath, Andrew C. ;
Knight, Rob ;
Gordon, Jeffrey I. .
NATURE, 2009, 457 (7228) :480-U7
[40]   SEGMENTED FILAMENTOUS BACTERIA ARE INDIGENOUS INTESTINAL BACTERIA THAT ACTIVATE INTRAEPITHELIAL LYMPHOCYTES AND INDUCE MHC CLASS-II MOLECULES AND FUCOSYL ASIALO GM1 GLYCOLIPIDS ON THE SMALL-INTESTINAL EPITHELIAL-CELLS IN THE EX-GERM-FREE MOUSE [J].
UMESAKI, Y ;
OKADA, Y ;
MATSUMOTO, S ;
IMAOKA, A ;
SETOYAMA, H .
MICROBIOLOGY AND IMMUNOLOGY, 1995, 39 (08) :555-562