Abstract
Chronic wounds cause significant patient morbidity and mortality. A key factor in their etiology is microbial infection, yet skin host-microbiota interactions during wound repair remain poorly understood. Microbiome profiles of noninfected human chronic wounds are associated with subsequent healing outcome. Furthermore, poor clinical healing outcome was associated with increased local expression of the pattern recognition receptor NOD2. To investigate NOD2 function in the context of cutaneous healing, we treated mice with the NOD2 ligand muramyl dipeptide and analyzed wound repair parameters and expression of antimicrobial peptides. Muramyl dipeptide treatment of littermate controls significantly delayed wound repair associated with reduced re-epithelialization, heightened inflammation, and up-regulation of murine β-defensins 1, 3, and particularly 14. We postulated that although murine β-defensin 14 might affect local skin microbial communities, it may further affect other healing parameters. Indeed, exogenously administered murine β-defensin 14 directly delayed mouse primary keratinocyte scratch wound closure invitro. To further explore the role of murine β-defensin 14 in wound repair, we used Defb14-/- mice and showed they had a global delay in healing invivo, associated with alterations in wound microbiota. Taken together, these studies suggest a key role for NOD2-mediated regulation of local skin microbiota, which in turn affects chronic wound etiology.
Highlights
Chronic wounds, which include pressure sores and venous and diabetic foot ulcers (DFUs), are a global problem leading to substantial morbidity and mortality (Gottrup, 2004)
Human chronic wound microbiome is linked to healing outcome Patients were recruited with chronic noninfected DFUs
Patients were separated into two groups according to their time to heal over a period of 12 weeks; DFU healed in 7 weeks or less (n 1⁄4 10) versus nonhealed at 12 weeks or longer (n 1⁄4 9)
Summary
Chronic wounds, which include pressure sores and venous and diabetic foot ulcers (DFUs), are a global problem leading to substantial morbidity and mortality (Gottrup, 2004). Skin-resident microbiota and pathogenic species may colonize the wound and proliferate (Eming et al, 2014). Poor progression of chronic wounds is often associated with infection and the presence of recalcitrant microbial biofilms comprising Staphylococcus, Pseudomonas, and Corynebacterium species and a variety of other organisms PRRs respond to highly conserved microbial structures: pathogen-associated molecular patterns that can trigger inflammatory and defense responses such as keratinocyte-mediated production of antimicrobial peptides (AMPs). The skin has many AMPs, including cathelicidins, b-defensins, S100A15, RNase-7, and histones (Buchau et al., 2007; Dorschner et al, 2001; Gallo and Hooper, 2012; Halverson et al, 2015; Simanski et al, 2010; Sorensen et al, 2006; Yang et al, 2017) and induces members of the b-defensin family under conditions of inflammation, infection, and wound healing (Mangoni et al, 2016; Schneider et al, 2005)
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