Abstract
BackgroundTreatment of cutaneous wounds with poly-N-acetyl-glucosamine nanofibers (sNAG) results in increased kinetics of wound closure in diabetic animal models, which is due in part to increased expression of several cytokines, growth factors, and innate immune activation. Defensins are also important for wound healing and anti-microbial activities. Therefore, we tested whether sNAG nanofibers induce defensin expression resulting in bacterial clearance.MethodologyThe role of sNAG in defensin expression was examined using immunofluoresence microscopy, pharmacological inhibition, and shRNA knockdown in vitro. The ability of sNAG treatment to induce defensin expression and bacterial clearance in WT and AKT1−/− mice was carried out using immunofluoresent microscopy and tissue gram staining. Neutralization, using an antibody directed against β-defensin 3, was utilized to determine if the antimicrobial properties of sNAG are dependent on the induction of defensin expression.Conclusions/FindingssNAG treatment causes increased expression of both α- and β-type defensins in endothelial cells and β-type defensins in keratinocytes. Pharmacological inhibition and shRNA knockdown implicates Akt1 in sNAG-dependent defensin expression in vitro, an activity also shown in an in vivo wound healing model. Importantly, sNAG treatment results in increased kinetics of wound closure in wild type animals. sNAG treatment decreases bacterial infection of cutaneous wounds infected with Staphylococcus aureus in wild type control animals but not in similarly treated Akt1 null animals. Furthermore, sNAG treatment of S. aureus infected wounds show an increased expression of β-defensin 3 which is required for sNAG-dependent bacterial clearance. Our findings suggest that Akt1 is involved in the regulation of defensin expression and the innate immune response important for bacterial clearance. Moreover, these findings support the use of sNAG nanofibers as a novel method for enhancing wound closure while simultaneously decreasing wound infection.
Highlights
Wound infection is a major complication especially in patients with chronic disease such as diabetes or during immunosuppression
Our previously published results show that sNAG treatment of cutaneous wounds results in increased wound closure in a diabetic mouse model that is due at least in part to increased angiogenesis and keratinocyte proliferation and migration [14]
The findings presented here suggest the use of a marine diatom derived nanofiber, sNAG as a novel and effective method to enhance wound healing while concurrently decreasing wound infection
Summary
Wound infection is a major complication especially in patients with chronic disease such as diabetes or during immunosuppression Such patients have disruptions in appropriate inflammatory responses, including the migration and recruitment of neutrophils and macrophage, which predisposes them to increased infection [1]. Defensins are small (3–4 kDa), cysteine-rich cationic peptides found in mammals, insects, and plants that are classified into different families (a, b, and h) based on their pattern of disulfide bonding These small peptides are important effectors of innate immunity; possessing antimicrobial properties that are active against gram positive and negative bacteria, fungi, and many viruses. Given that defensins are part of the innate immune system, activation of pathways resulting in defensin expression and secretion will preclude the generation of resistant organisms as well as allow for the antibiotic-independent clearance of bacterial infection. We tested whether sNAG nanofibers induce defensin expression resulting in bacterial clearance
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