title: Interleukin-23 (IL-23), independent of IL-17 and IL-22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice.
abstract: Our objective was to determine the role of the inflammatory cytokine interleukin-23 (IL-23) in promoting neutrophil recruitment, inflammatory cytokine expression and intestinal histopathology in response to Clostridium difficile infection. Wild-type (WT) and p19(-/-) (IL-23KO) mice were pre-treated with cefoperazone in their drinking water for 5 days, and after a 2-day recovery period were challenged with spores from C. difficile strain VPI 10463. Interleukin-23 deficiency was associated with significant defects in both the recruitment of CD11b(High) Ly6G(H) (igh) neutrophils to the colon and the expression of neutrophil chemoattractants and stabilization factors including Cxcl1, Cxcl2, Ccl3 and Csf3 within the colonic mucosa as compared with WT animals. Furthermore, the expression of inflammatory cytokines including Il33, Tnf and Il6 was significantly reduced in IL-23-deficient animals. There was also a trend towards less severe colonic histopathology in the absence of IL-23. The induction of Il17a and Il22 was also significantly abrogated in IL-23KO mice. Inflammatory cytokine expression and neutrophilic inflammation were not reduced in IL-17a-deficient mice or in mice treated with anti-IL-22 depleting monoclonal antibody. However, induction of RegIIIg was significantly reduced in animals treated with anti-IL-22 antibody. Taken together, these data indicate that IL-23, but not IL-17a or IL-22, promotes neutrophil recruitment and inflammatory cytokine and chemokine expression in the colon in response to C. difficile 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: 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: 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: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016360:Clostridioides difficile / Q000276:immunology* / Q000472:pathogenicity; D003106:Colon / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; C490255:Reg3g protein, mouse
keywords: Clostridium difficile; colitis; innate inflammation; mucosal inflammation; neutrophils