title: Role of interferon-γ and inflammatory monocytes in driving colonic inflammation during acute Clostridium difficile infection in mice.
abstract: The inflammatory response to the colonic pathogen Clostridium difficile is characterized by the induction of inflammatory cytokines including Interleukin-23 (IL-23) and interferon-γ (IFN-γ) and the recruitment of myeloid cells including Ly6CHighmonocytes. IL-23 knockout mice showed reduced expression of the monocyte chemokines Ccl4 and Ccl7, but not Ccl2, as well as reduced Ly6CHighLy6GMidmonocyte recruitment to the colon in response to C. difficile colitis. Clostridium difficile-infected CCR2-/-(CCR2 KO) mice showed a significant defect in Ly6CHighLy6GMidmonocyte recruitment to the colon in response to C. difficile. Although there was no decrease in expression of the inflammatory cytokines Il1b, Il6 or Tnf or reduction in the severity of colonic histopathology associated with ablation of monocyte recruitment, Slpi and Inos expression was significantly reduced in the colons of these animals. Additionally, neutralization of IFN-γ through the administration of anti-IFN-γ monoclonal antibody resulted in a significant reduction in the expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10, but not a reduction in the neutrophil chemokines Cxcl1, Cxcl2 and Ccl3 or the monocyte chemokine Ccl2. Consistently, monocyte and neutrophil recruitment were unchanged following anti-IFN-γ treatment. Additionally, Inos and Slpi expression were unchanged following anti-IFN-γ treatment, suggesting that Inos and Slpi regulation is independent of IFN-γ during C. difficile colitis. Taken together, these data strongly suggest that IL-23 and CCR2 signalling are required for monocyte recruitment during C. difficile colitis. Additionally, these studies also suggest that monocytes, but not IFN-γ, are necessary for full expression of Inos and Slpi in the colon.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McDermott
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Falkowski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Roderick A
authors.initials: RA
authors.lastname: McDonald
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Frank
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Chinmay R
authors.initials: CR
authors.lastname: Pandit
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.|Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.|Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
mesh_terms: D000208:Acute Disease; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000950:Antigens, Ly / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016360:Clostridioides difficile / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D000950:Antigens, Ly; C515335:Ccr2 protein, mouse; D018925:Chemokines; D018836:Inflammation Mediators; D053759:Interleukin-23; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D007371:Interferon-gamma
keywords: bacterial; cytokines; inflammation; mucosa