Mechanisms of Neutrophil Recruitment and Immunopathology During Acute Clostridium difficile Colitis.
dc.contributor.author | McDermott, Andrew J. | en_US |
dc.date.accessioned | 2015-09-30T14:22:37Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2015-09-30T14:22:37Z | |
dc.date.issued | 2015 | en_US |
dc.date.submitted | 2015 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/113375 | |
dc.description.abstract | C. difficile infection in mice is associated with acute colitis characterized by the induction of inflammatory cytokines, intestinal histopathology, and robust neutrophil recruitment. Our objective was to determine the roles of the inflammatory cytokines GM-CSF, TNFa, IL-23, IL-22, and IL-17a in promoting neutrophil recruitment and innate inflammation in response to C. difficile infection. Ablation of GM-CSF signaling in vivo using a depleting anti-GM-CSF mAb was associated with significant reduction in colonic expression of Il1b, Tnfa, and Inos. Furthermore, expression of the neutrophil chemotactic factors Cxcl1 and Cxcl2 was also reduced in the colonic mucosa of anti-GM-CSF treated mice. Notably, anti-GM-CSF treatment did not affect intestinal histopathology. Direct reduction in neutrophil recruitment through the use of a depleting anti-Gr-1 antibody was not associated with reduction in the host inflammatory response. Colonic expression of inflammatory cytokines, including Tnfa, Il6, and Il33, and the neutrophil chemotactic factors Cxcl1 and Cxcl2 was unchanged following anti-Gr-1 treatment. Furthermore, colonic histopathology was no attenuated in anti-Gr-1 treated mice. Ablation of TNFa signaling was associated with increased inflammatory cytokine expression. While anti-TNFa treatment did not reduced neutrophil recruitment or expression of Cxcl1 and Cxcl2, the expression of numerous inflammatory cytokines including Il1b and Il6 were increased in anti TNFa-treated mice. Additionally, anti-TNFa treatment was associated with the development of more severe colonic histopathology following C. difficile infection. IL-23 deficiency was associated with significantly decreased neutrophil recruitment. Concomitant with the reduced neutrophilic influx, the expression of the neutrophil-recruiting chemokines Cxcl1, Cxcl2, and Ccl3 was also significantly reduced. IL-17 and IL-22 expression were also significantly reduced in the absence of IL-23, as was expression of the antimicrobial peptide RegIIIg. Furthermore, the induction of inflammatory cytokines including Tnfa, Il33, and Il6 was significantly reduced in IL-23-/- mice. Inflammatory cytokine expression and neutrophilic inflammation were not reduced in IL-17a-deficient mice or in mice treated with anti-IL-22 depleting mAb. However, RegIIIg expression was significantly reduced in anti-IL-22 treated animals. Taken together these data suggest that IL-23 and GM-CSF, independent of IL-17a, IL-22, and TNFa, drive neutrophil recruitment and inflammatory | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Colitis | en_US |
dc.subject | Mucosal Inflammation | en_US |
dc.subject | Neutrophil Recruitment | en_US |
dc.subject | Clostridium difficile | en_US |
dc.title | Mechanisms of Neutrophil Recruitment and Immunopathology During Acute Clostridium difficile Colitis. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Microbiology and Immunology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Huffnagle, Gary | en_US |
dc.contributor.committeemember | Kao, John Y. | en_US |
dc.contributor.committeemember | Young, Vincent Bensan | en_US |
dc.contributor.committeemember | Hanna, Philip | en_US |
dc.subject.hlbsecondlevel | Microbiology and Immunology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/113375/1/mcderand_1.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/113375/2/mcderand_3.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/113375/3/mcderand_2.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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