title: Complement-dependent injury and protection in a murine model of acute dextran sulfate sodium-induced colitis.
abstract: Complement plays a key role in the pathophysiology of many inflammatory diseases, and in this study, we investigated the role of complement in the pathogenesis of inflammatory bowel disease. Compared to wild-type mice, mice deficient in C3 or factor B were protected from acute dextran sulfate sodium (DSS)-induced colitis. C1q/mannose-binding lectin (MBL) double-deficient mice, however, exhibited more severe colitis than wild-type mice. When mice were allowed to recover after DSS treatment, all C1q/MBL(-/-) mice died by day 2 of recovery period, and, surprisingly, all C3(-/-) and factor B(-/-) mice died by day 5. Serum endotoxin levels were significantly increased in complement-deficient mice prior to death, particularly in C1q/MBL(-/-) mice, and antibiotic treatment prevented the lethal effect of DSS in all complement-deficient mice. In contrast to complement deficiency, targeted complement inhibition with either complement receptor 2 (CR2)-Crry (blocks all pathways at C3 activation) or CR2-factor H (blocks alternative pathway) was highly protective at treating established acute colitis. Endotoxin levels remained low in complement-inhibited mice, and complement inhibition also reduced inflammatory cytokines, leukocyte infiltration, and tissue injury while improving wound repair and mucosal healing. CR2-factor H provided more effective protection than CR2-Crry. Thus, complement has both pathogenic and protective roles in acute DSS-induced colitis, and whereas the alternative pathway appears to play a key role in tissue inflammation and injury, the classical/lectin pathway provides important protection in terms of host defense and wound repair. Targeted inhibition of the alternative pathway may represent a therapeutic modality for treating acute phases of inflammatory bowel disease.
authors.affiliation: Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schepp-Berglind
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Michelle
authors.initials: M
authors.lastname: Elvington
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Peter
authors.initials: P
authors.lastname: Mannon
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D003167:Complement Activation / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D003165:Complement System Proteins; D016264:Dextran Sulfate