Immunomodulatory Role of Cathelicidin at Colonic Epithelium

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dc.contributor.advisorCobo, Eduardo R.
dc.contributor.authorHolani, Ravi
dc.contributor.committeememberProud, David
dc.contributor.committeememberBarkema, Herman W.
dc.contributor.committeememberVogel, Hans J.
dc.date2020-06
dc.date.accessioned2020-03-26T15:31:02Z
dc.date.available2020-03-26T15:31:02Z
dc.date.issued2020-03-23
dc.description.abstractCathelicidin, a small, cationic and amphiphilic host defense peptide, is expressed by hematopoietic and non-hematopoietic cells. Initially considered an antimicrobial, cathelicidin are more than simply natural antibiotics. Due to their ability to interact with multiple receptors, cathelicidin can modulate immune responses by a variety of host cells. However, their immunomodulatory effects vary based on their micro-environment, including tissue type (hematopoietic vs. non-hematopoietic), availability of microbes or associated factor(s) and effective concentration of cathelicidin. Since most studies are performed in leukocytes, ability of cathelicidin to regulate immune responses by intestinal epithelium remains largely unknown. The objective was to elucidate immunomodulatory potential of cathelicidin in colonic epithelium, under homeostasis as well as during bacterial colitis. In the first study, we determined how cathelicidin synergized with lipopolysaccharide or Salmonella enterica Typhimurium to enhance production of neutrophil chemokine CXCL8 (human) or murine CXCL1 (functional homologue of CXCL8). Further, we identified a two-signal mechanism triggered by the complex of LPS-LL37, in which nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling was involved in CXCL8 mRNA synthesis, whereas p38 mitogen-activated protein kinase (p38MAPK) was involved in CXCL8 mRNA stabilization. In a Citrobacter rodentium model of colitis, we corroborated increased synthesis of CXCL1 chemokine, effective neutrophil recruitment and reduced bacterial burden in Camp+/+ versus Camp-/- (cathelicidin null) mice. In the second study, under physiological conditions, cathelicidin induced synthesis of Toll-like receptor (TLR) negative regulator, Toll-interacting protein (Tollip). This induced Tollip production inhibited TLR-mediated apoptosis in colonic epithelium, both in vitro by cytokines tumour necrosis factor- α and interferon- γ as well as in vivo in a C. rodentium model of colitis. In conclusion, cathelicidin regulated colonic innate immunity via reduction of unwarranted inflammation by inhibiting TLR responses through Tollip, while promoting a neutrophil response to infection.en_US
dc.identifier.citationHolani, R. (2020). Immunomodulatory Role of Cathelicidin at Colonic Epithelium (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37645
dc.identifier.urihttp://hdl.handle.net/1880/111750
dc.language.isoengen_US
dc.publisher.facultyVeterinary Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectColonic epitheliumen_US
dc.subjectCathelicidinsen_US
dc.subjectLipopolysaccharideen_US
dc.subjectCXCL8/CXCL1en_US
dc.subjectSalmonella spp.en_US
dc.subjectCitrobacter rodentiumen_US
dc.subjectTollipen_US
dc.subjectApoptosisen_US
dc.subjectmiRNAen_US
dc.subject.classificationMicrobiologyen_US
dc.subject.classificationVeterinary Scienceen_US
dc.subject.classificationImmunologyen_US
dc.titleImmunomodulatory Role of Cathelicidin at Colonic Epitheliumen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineVeterinary Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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