UBC Theses and Dissertations
Synthetic host defense peptides as therapies for skin inflammation and biofilms Wu, Bing
Novel treatments for inflammatory skin disorders are of great demand as sterile inflammatory skin diseases such as psoriasis and atopic dermatitis are common, long-lasting, and detrimental to people’s quality of life, yet have no cure. Skin biofilm infections caused by Staphylococcus aureus and Pseudomonas aeruginosa are intrinsically and adaptively resistant to antimicrobial agents but lack specific treatments. Natural and synthetic host defense peptides are known to exhibit beneficial biological functions including direct antimicrobial, antibiofilm, immunomodulatory and anti-inflammatory properties. Therefore, I proposed that anti-inflammatory peptide IDR-1002 and antibiofilm peptide DJK-5 could tackle skin inflammation by different underlying mechanisms. IDR-1002 was shown to have promising in vitro and in vivo anti-inflammatory effects. In an animal model, it dampened PMA-induced ear edema, proinflammatory cytokine and reactive oxygen and nitrogen species release and neutrophil recruitment by downregulating G-protein coupled receptors that recognize proinflammatory mediators. IDR-1002 also suppressed the IFN-γ pathway and an interferon regulatory factor-8-regulated network in PMA-induced inflammation. Similarly, lipidated peptidomimetics Pam-(Lys-βNspe)6-NH2 and Lau-(Lys-βNspe)6-NH2 were potent suppressors of PMA-induced sterile skin inflammation comparable to the non-steroidal anti-inflammatory drug indomethacin. To study biofilm skin infection, I established an air-liquid interface epidermal model and showed that DJK-5 significantly reduced 1-day and 3-day Methicillin-resistant S. aureus (MRSA) and P. aeruginosa biofilms. Using this in vivo-like humanized system as a screening platform allowed the identification of novel peptides D-3006 and D-3007 with superior antibiofilm activity and immunomodulatory potential. Skin with thermal wounds had increased susceptibility to MRSA biofilm infection, and DJK-5 treatment significantly reduced bacterial load, cytotoxicity, and pro-inflammatory cytokines. Combination treatment of DJK-5 with IDR-1002 further reduced cytotoxicity and skin inflammation. Transcriptomic analysis revealed that DJK-5 treatment restored skin barrier function, suppressed MRSA intracellular invasion, and dampened TNF-α signalling and transcription factors AP-1, c/EBPB and CREB, leading to reduced production of proinflammatory mediators such as cytokines, prostaglandins, and matrix metalloproteinases. Both IDR-1002 and DJK-5 returned skin to homeostasis by downregulating TNF-α and NF-κB signalling and their negative regulators, and upregulating TSC22D3, an important mediator of glucocorticoid anti-inflammatory effects. These data reveal the intrinsic promise of synthetic peptides in treating inflammation and biofilm infections.
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