title: Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa during Clostridium difficile infection in mice.
abstract: Clostridium difficile infection in antibiotic-treated mice results in acute colitis characterized by severe intestinal histopathology, robust neutrophil influx, and increased expression of numerous inflammatory cytokines, including GM-CSF. We utilized a neutralizing monoclonal antibody (mAb) against GM-CSF in a murine model to study the role of GM-CSF during acute C. difficile colitis. Cefoperazone-treated mice were challenged with C. difficile (strain 630) spores. Expression of GM-CSF was significantly increased in animals challenged with C. difficile. Treatment with an anti-GM-CSF mAb did not alter C. difficile colonization levels, weight loss, or expression of IL-22 and RegIIIγ. However, expression of the inflammatory cytokines TNFα and IL-1β, as well as iNOS, was significantly reduced following anti-GM-CSF treatment. Expression of the neutrophil chemokines CXCL1 and CXCL2, but not the chemokines CCL2, CCL4, CXCL9, and CXCL10, was significantly reduced by anti-GM-CSF treatment. Consistent with a decrease in neutrophil-attractant chemokine expression, there were fewer neutrophils in histology sections and a reduction in the expression of secretory leukocyte protease inhibitor (SLPI), a tissue anti-protease that protects against damage by secreted neutrophil elastase. These data indicate that GM-CSF plays a role in the inflammatory signaling network that drives neutrophil recruitment in response to C. difficile infection but does not appear to play a role in clearance of the infection.
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: 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: 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: 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: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000276:immunology; D002438:Cefoperazone / Q000008:administration & dosage; D016360:Clostridioides difficile / Q000276:immunology*; D003015:Clostridium Infections / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D002438:Cefoperazone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: bacteria; chemokine; colitis; cytokine; epithelium; inflammation; innate immunity; microbiome