Regulation of airway inflammation: interplay of cytokine IL-17A/F & human host defence peptide cathelicidin LL-37
| dc.contributor.author | Altieri, Anthony | |
| dc.contributor.examiningcommittee | Uzonna, Jude (Immunology) | en_US |
| dc.contributor.examiningcommittee | Murooka, Thomas (Immunology) | en_US |
| dc.contributor.examiningcommittee | Fowke, Keith (Medical Microbiology & Infectious Diseases) | en_US |
| dc.contributor.examiningcommittee | Bevins, Charles (UC Davis School of Medicine) | en_US |
| dc.contributor.supervisor | Mookherjee, Neeloffer | |
| dc.date.accessioned | 2022-08-31T14:58:27Z | |
| dc.date.available | 2022-08-31T14:58:27Z | |
| dc.date.copyright | 2022-08-23 | |
| dc.date.issued | 2022-08-15 | |
| dc.date.submitted | 2022-08-23T14:58:23Z | en_US |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Asthma is a heterogeneous disease. The inhaled allergen-mediated disease phenotype is either Th2-high or Th2-low/Th17-high. The Th2-low/Th17-high phenotype is predominantly associated with neutrophilic inflammation and steroid-unresponsive severe asthma, for which there are no current treatments. Th17-driven neutrophilic airway inflammation is characterized by the concurrent increase of pro-inflammatory cytokine IL-17A/F and immunomodulatory cationic host defence peptide (CHDP) LL-37 in the lungs. However, the effect of LL-37 on IL-17A/F-mediated protein changes and signaling networks in airway inflammation is poorly understood. Therefore, I examined the immunomodulatory activity of LL-37 on IL-17A/F-mediated airway inflammation. I performed proteomic profiling to characterize IL-17A/F-mediated inflammation (in the presence/absence of other pro-inflammatory cytokines, such as TNF-a) in human bronchial epithelial cells (HBEC) and demonstrated that IL-17A/F-mediated inflammation leads to enhancement of secreted proteins, including the CHDP Lipocalin (LCN)-2 and neutrophilic chemokine GROa, which promote neutrophil migration in the context of airway inflammation. These protein targets were used to define the immunomodulatory role of cathelicidin LL-37 in IL-17A/F-driven inflammation. I demonstrated that cathelicidin LL-37 suppressed IL-17A/F-mediated LCN-2 production in HBEC. Further, I demonstrated that LL-37 was negatively correlated with LCN-2 and neutrophil accumulation in the lungs of a mouse model characterized by IL-17-driven neutrophilic airway inflammation. Moreover, I demonstrated that LL-37 suppressed the abundance of transcription factor CEBPB mRNA and enhanced the abundance of the RNA-binding protein (RBP) Regnase-1, which are positive and negative regulators of IL-17A/F-mediated LCN-2 production in HBEC, respectively. Taken together, these findings suggest that LL-37 simultaneously alters the transcriptional and post-transcriptional machinery to limit IL-17A/F-mediated neutrophil accumulation in the lung. In subsequent studies I demonstrated that citrullination, a relevant post-translational modification of LL-37 occurring in the lung, results in the selective loss of NFKBIZ mRNA abundance increases in the presence of IL-17A/F, as well as dampened GROa and CCL20 production in combination with IL-17A/F, compared to native LL-37. These findings suggest that citrullination limits the pro-inflammatory activity of LL-37. Overall, the proteins I identified in this study to be altered by IL-17A/F and/or LL-37 may represent pivotal checkpoints in neutrophilic airway inflammation and can be examined to develop new therapeutic strategies. | en_US |
| dc.description.note | October 2022 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36816 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | LL-37 | en_US |
| dc.subject | IL-17A/F | en_US |
| dc.subject | Airway Inflammation | en_US |
| dc.subject | Asthma | en_US |
| dc.subject | Cationic Host Defence Peptides | en_US |
| dc.subject | Cytokines | en_US |
| dc.subject | Bronchial Epithelial Cells | en_US |
| dc.title | Regulation of airway inflammation: interplay of cytokine IL-17A/F & human host defence peptide cathelicidin LL-37 | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no | en_US |