title: Systemic macrophage depletion inhibits Helicobacter bilis-induced proinflammatory cytokine-mediated typhlocolitis and impairs bacterial colonization dynamics in a BALB/c Rag2-/- mouse model of inflammatory bowel disease.
abstract: Helicobacter bilis, an enterohepatic helicobacter, is associated with chronic hepatitis in aged immunocompetent inbred mice and inflammatory bowel disease (IBD) in immunodeficient mice. To evaluate the role of macrophages in H. bilis-induced IBD, Rag2(-/-) BALB/c or wild-type (WT) BALB/c mice were either sham dosed or infected with H. bilis Missouri strain under specific-pathogen-free conditions, followed by an intravenous injection of a 0.2-ml suspension of liposomes coated with either phosphate-buffered saline (control) or clodronate (a macrophage depleting drug) at 15 weeks postinfection (wpi). At 16 wpi, the ceca of H. bilis-infected Rag2(-/-) mice treated with control liposomes had significantly higher histopathological lesional scores (for cumulative typhlitis index, inflammation, edema, epithelial defects, and hyperplasia) and higher counts of F4/80(+) macrophages and MPO(+) neutrophils compared to H. bilis-infected Rag2(-/-) mice treated with clodronate liposomes. In addition, cecal quantitative PCR analyses revealed a significant suppression in the expression of macrophage-related cytokine genes, namely, Tnfa, Il-1β, Il-10, Cxcl1, and iNos, in the clodronate-treated H. bilis-infected Rag2(-/-) mice compared to the H. bilis-infected Rag2(-/-) control mice. Finally, cecal quantitative PCR analyses also revealed a significant reduction in bacterial colonization in the clodronate-treated Rag2(-/-) mice. Taken together, our results suggest that macrophages are critical inflammatory cellular mediators for promoting H. bilis-induced typhlocolitis in mice.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. smuthu01@mit.edu
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Barry
authors.initials: B
authors.lastname: Rickman
authors.forename: Melissa
authors.initials: M
authors.lastname: Mobley
authors.forename: Amanda
authors.initials: A
authors.lastname: McCabe
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D003092:Colitis / Q000150:complications / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D016998:Helicobacter / Q000145:classification / Q000254:growth & development* / Q000276:immunology; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D018836:Inflammation Mediators; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; C499308:Rag2 protein, mouse; D004002:Clodronic Acid; D016753:Interleukin-10