Regulation of the alternative pathway of complement modulates injury and immunity in a chronic model of dextran sulphate sodium-induced colitis

被引:28
作者
Elvington, M. [1 ]
Schepp-Berglind, J. [1 ]
Tomlinson, S. [1 ,2 ]
机构
[1] Med Univ S Carolina, Dept Microbiol & Immunol, Childrens Res Inst, Charleston, SC 29425 USA
[2] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA
基金
美国国家卫生研究院;
关键词
colon; complement; inflammation; inflammatory bowel disease; INFLAMMATORY-BOWEL-DISEASE; DECAY-ACCELERATING FACTOR; ULCERATIVE-COLITIS; ACTIVATED COMPLEMENT; DENDRITIC CELLS; CROHNS-DISEASE; MURINE MODEL; C5A; EXPRESSION; SUSCEPTIBILITY;
D O I
10.1111/cei.12464
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The role of complement in inflammatory bowel disease (IBD) has been studied primarily using acute models, and it is unclear how complement affects processes in more relevant chronic models of IBD in which modulation of adaptive immunity and development of fibrosis have pathogenic roles. Using mice deficient in C1q/mannose-binding lectin (MBL) or C3, we demonstrated an important role for these opsonins and/or the classical pathway C3 convertase in providing protection against mucosal injury and infection in a model of chronic dextran sulphate sodium (DSS)-induced colitis. In contrast, deficiency of the alternative pathway (fB(-/-) mice) had significantly less impact on injury profiles. Consequently, the effect of a targeted inhibitor of the alternative pathway was investigated in a therapeutic protocol. Following the establishment of colitis, mice were treated with CR2-fH during subsequent periods of DSS treatment and acute injury (modelling relapse). CR2-fH significantly reduced complement activation, inflammation and injury in the colon, and additionally reduced fibrosis. Alternative pathway inhibition also altered the immune response in the chronic state in terms of reducing numbers of B cells, macrophages and mature dendritic cells in the lamina propria. This study indicates an important role for the alternative pathway of complement in the pathogenesis and the shaping of an immune response in chronic DSS-induced colitis, and supports further investigation into the use of targeted alternative pathway inhibition for the treatment of IBD.
引用
收藏
页码:500 / 508
页数:9
相关论文
共 34 条
[1]   Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells [J].
Abe, Kazumichi ;
Nguyen, Kim Phung ;
Fine, Sean D. ;
Mo, Ji-Hun ;
Shen, Carol ;
Shenouda, Steve ;
Corr, Maripat ;
Jung, Steffen ;
Lee, Jongdae ;
Eckmann, Lars ;
Raz, Eyal .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (43) :17022-17027
[2]   ENHANCED LOCAL PRODUCTION OF COMPLEMENT COMPONENTS IN THE SMALL-INTESTINES OF PATIENTS WITH CROHNS-DISEASE [J].
AHRENSTEDT, O ;
KNUTSON, L ;
NILSSON, B ;
NILSSONEKDAHL, K ;
ODLIND, B ;
HALLGREN, R .
NEW ENGLAND JOURNAL OF MEDICINE, 1990, 322 (19) :1345-1349
[3]   Distinct Cytokine Patterns Identified from Multiplex Profiles of Murine DSS and TNBS-induced Colitis [J].
Alex, Philip ;
Zachos, Nicholas C. ;
Nguyen, Thuan ;
Gonzales, Liberty ;
Chen, Tian-E ;
Conklin, Laurie S. ;
Centola, Michoel ;
Li, Xuhang .
INFLAMMATORY BOWEL DISEASES, 2009, 15 (03) :341-352
[4]   Neutralization of complement component C5 ameliorates the development of dextran sulfate sodium (DSS)-colitis in mice [J].
Aomatsu, Tomoki ;
Imaeda, Hirotsugu ;
Takahashi, Kenichiro ;
Fujimoto, Takehide ;
Kasumi, Eiji ;
Ban, Hiromitsu ;
Bamba, Shigeki ;
Yoden, Atsushi ;
Tamai, Hiroshi ;
Fujiyama, Yoshihide ;
Andoh, Akira .
JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, 2013, 52 (01) :72-75
[5]   Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection [J].
Atkinson, C ;
Song, HB ;
Lu, B ;
Qiao, F ;
Burns, TA ;
Holers, VM ;
Tsokos, GC ;
Tomlinson, S .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (09) :2444-2453
[6]   Evaluation of chemical mediators and cellular response during acute and chronic gut inflammatory response induced by dextran sodium sulfate in mice [J].
Bento, Allisson Freire ;
Pereira Leite, Daniela Ferraz ;
Marcon, Rodrigo ;
Claudino, Rafaela Franco ;
Dutra, Rafael Cypriano ;
Cola, Maira ;
Martini, Alessandra Cadete ;
Calixto, Joao B. .
BIOCHEMICAL PHARMACOLOGY, 2012, 84 (11) :1459-1469
[7]   Expression of cell membrane complement regulatory glycoproteins along the normal and diseased human gastrointestinal tract [J].
Berstad, AE ;
Brandtzaeg, P .
GUT, 1998, 42 (04) :522-529
[8]   Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis [J].
Chen, Guojiang ;
Yang, Yuemei ;
Gao, Xudong ;
Dou, Yan ;
Wang, Huihui ;
Han, Gencheng ;
Wang, Renxi ;
Wang, Jianan ;
Wang, Liyan ;
Li, Xinying ;
Guo, Renfeng ;
Xiao, He ;
Shen, Beifen ;
Li, Yan .
LABORATORY INVESTIGATION, 2011, 91 (03) :472-483
[9]  
Deguchi Y, 2005, INT J MOL MED, V16, P605
[10]   Lamina propria plasma cells in inflammatory bowel disease: Intracellular detection of immunoglobulins using flow cytometry [J].
Dorn, I ;
Schlenke, P ;
Mascher, B ;
Stange, EF ;
Seyfarth, M .
IMMUNOBIOLOGY, 2002, 206 (05) :546-557