Marshall, Courtney2026-09-022026-09-022026-08-202026-08-20http://hdl.handle.net/1993/40051Allergic asthma is a chronic inflammatory respiratory disease that affects roughly 10-15% of the population. There is also a significant sex bias in asthma whereby after puberty, females experience higher prevalence and greater severity of asthma. Consequently, the patients whose asthma remains uncontrolled despite available therapeutics like corticosteroids, which represent ~24% of patients, are more often females. Moreover, corticosteroids can increase a patient’s susceptibility to lung infections, which exacerbate asthma. Therefore, novel therapeutics are needed to alleviate airway inflammation in asthma ideally without compromising resolution of infections. We previously showed that a synthetic derivative of antimicrobial host defence peptide known as Innate Defence Regulator (IDR) peptide, IDR-1002, alleviates allergen house dust mite (HDM)-mediated airway inflammation in the lungs of female mice, which was dependent on the suppression of IL-33. However, the mechanisms of suppression of IL-33 and the sex-related differences in the modulation of airway inflammation by IDR-1002 remain unknown. Therefore, in this thesis, I examined the mechanisms of IL-33 suppression by IDR-1002 and the immunomodulatory functions of IDR-1002 in HDM-challenged females and males. I showed that IDR-1002 enhanced an mRNA binding protein tristetraprolin (TTP) and its activator, mitogen-activated protein kinase (MKP)-1, prior to the suppression of IL-33 mRNA and protein, in human bronchial epithelial cells (HBEC). In addition to IL-33, IDR-1002 suppressed other well-defined TTP targets, namely TNF, IL-1, IL-6, LIF, MIP-1, and IP-10 in the lungs of HDM-challenged female mice, suggesting that IDR-1002 enhances a post-transcriptional machinery to regulate inflammation. I then characterized the broad transcriptomic changes elicited by IDR-1002, in the presence and absence of interferon (IFN) (which induces IL-33) in HBEC. IDR-1002 upregulated 35 and downregulated 36 genes and these changes were represented by biological processes associated with the major histocompatibility complex (MHC) II and viral response. CD40 and MHCII proteins were confirmed to be downregulated by IDR-1002. These results identified a novel immunomodulatory function of IDR-1002 to alter antigen presentation at the epithelial interface. I next defined the sex-related differences in HDM-mediated changes to the lung tissue proteome, serum sex steroids, and their pulmonary receptors, in a mouse model. I determined that females and males exhibit disparate lung tissue proteomes as baseline, and in response to HDM. A total of 12 proteins were significantly altered in both males and females following HDM challenge, but these also showed a significant sex and exposure interaction, including tight junction protein (TJP)-1, an epithelial barrier protein that was more downregulated in females. Additionally, HDM challenge enhanced the serum abundance of progesterone and 17-estradiol in females, along with estrogen receptor (ER) abundance but decreased progesterone receptor (PR) in the lung tissue. In contrast, HDM-challenged males showed decreased serum testosterone and PR abundance in the lung tissue, but enhanced ER abundance in the lungs. Together, these results showed that females and males exhibit disparate responses to allergen, leading to different inflammatory milieus that may impact the function of IDR-1002. Finally, I examined the sex-related differences in the immunomodulation of HDM-challenged airway inflammation by IDR-1002. I showed that IDR-1002 suppresses HDM-induced type 2 inflammatory outcomes like HDM-specific IgE in the serum, and inflammatory cells along with IL-4, IL-5, and IL-13 in the lungs of both females and males. This was despite IL-33 not being suppressed by IDR-1002 in males, suggesting that underlying mechanisms of airway inflammation may be different. Together, the findings of this thesis provide indication that despite sex-related differences in response to allergens, there are common targetable pathways to control airway inflammation. This thesis adds new knowledge to advance the immunobiology of IDR peptides.engInflammationAsthmaAirway InflammationIL-33LungHost Defence PeptidesInnate Defence Regulator PeptidesSexBiological Sex