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1.
J Invest Dermatol ; 142(4): 1206-1216.e8, 2022 04.
Article in English | MEDLINE | ID: mdl-34710388

ABSTRACT

Nonhealing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of prohealing mechanisms is invaluable. The enzyme arginase1 (ARG1) is involved in prohealing responses, with its role in macrophages best characterized. ARG1 is also expressed by keratinocytes; however, ARG1 function in these critical wound repair cells is not understood. We characterized ARG1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal ARG1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte-specific ARG1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration, and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor N(omega)-hydroxy-nor-L-arginine, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in ARG1 activity through the addition of putrescine proved beneficial in wound closure. In summary, we show that epidermal ARG1 plays, to our knowledge, a previously unreported intrinsic role in cutaneous healing, highlighting epidermal ARG1 and the downstream mediators as potential targets for the therapeutic modulation of wound repair.


Subject(s)
Arginase , Skin Abnormalities , Animals , Arginase/genetics , Arginase/metabolism , Epidermis/metabolism , Keratinocytes/metabolism , Macrophages/metabolism , Mice , Mice, Knockout , Skin/metabolism , Skin Abnormalities/metabolism
2.
J Invest Dermatol ; 138(10): 2264-2274, 2018 10.
Article in English | MEDLINE | ID: mdl-29723492

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 ß-defensins 1, 3, and particularly 14. We postulated that although murine ß-defensin 14 might affect local skin microbial communities, it may further affect other healing parameters. Indeed, exogenously administered murine ß-defensin 14 directly delayed mouse primary keratinocyte scratch wound closure in vitro. To further explore the role of murine ß-defensin 14 in wound repair, we used Defb14-/- mice and showed they had a global delay in healing in vivo, 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.


Subject(s)
Microbiota/genetics , Nod2 Signaling Adaptor Protein/genetics , RNA/genetics , Up-Regulation , Wound Healing/genetics , Wounds and Injuries/genetics , beta-Defensins/genetics , Adult , Animals , Cells, Cultured , Disease Models, Animal , Female , Host Microbial Interactions , Humans , Keratinocytes/metabolism , Male , Mice , Mice, Inbred C57BL , Nod2 Signaling Adaptor Protein/metabolism , Real-Time Polymerase Chain Reaction , Transcriptional Activation , Wounds and Injuries/metabolism , Wounds and Injuries/pathology , beta-Defensins/metabolism
3.
J Invest Dermatol ; 137(11): 2427-2436, 2017 11.
Article in English | MEDLINE | ID: mdl-28647345

ABSTRACT

The skin microbiome exists in dynamic equilibrium with the host, but when the skin is compromised, bacteria can colonize the wound and impair wound healing. Thus, the interplay between normal skin microbial interactions versus pathogenic microbial interactions in wound repair is important. Bacteria are recognized by innate host pattern recognition receptors, and we previously showed an important role for the pattern recognition receptor NOD2 in skin wound repair. NOD2 is implicated in changes in the composition of the intestinal microbiota in Crohn's disease, but its role on skin microbiota is unknown. Nod2-deficient (Nod2-/-) mice had an inherently altered skin microbiome compared with wild-type controls. Furthermore, we found that Nod2-/- skin microbiome dominated and caused impaired healing, shown in cross-fostering experiments of wild-type pups with Nod2-/- pups, which then acquired altered cutaneous bacteria and delayed healing. High-throughput sequencing and quantitative real-time PCR showed a significant compositional shift, specifically in the genus Pseudomonas in Nod2-/- mice. To confirm whether Pseudomonas species directly impair wound healing, wild-type mice were infected with Pseudomonas aeruginosa biofilms and, akin to Nod2-/- mice, were found to exhibit a significant delay in wound repair. Collectively, these studies show the importance of the microbial communities in skin wound healing outcome.


Subject(s)
Microbiota/genetics , Nod2 Signaling Adaptor Protein/genetics , Pseudomonas aeruginosa/pathogenicity , Skin Diseases, Bacterial/pathology , Wound Healing/genetics , Animals , Biofilms , Biopsy, Needle , Disease Models, Animal , Gene Expression Regulation , Immunohistochemistry , Mice , Mice, Inbred C57BL , Random Allocation , Real-Time Polymerase Chain Reaction/methods , Skin Diseases, Bacterial/genetics , Wound Healing/physiology
4.
J Pathol ; 229(1): 121-31, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22951952

ABSTRACT

Infection is a significant causative factor in human chronic wounds that fail to heal. Complex innate host response mechanisms have evolved whereby potentially harmful pathogens are recognized by multiple host pattern recognition receptors (PRRs), yet understanding of PRR function, or dysfunction, in the context of chronic wounds remains limited. NOD2, a cytoplasmic PRR, has been strongly implicated in chronic inflammation of the gut, where loss-of-function mutations have been linked to Crohn's disease; however, cutaneous Nod2 function remains poorly characterized. Here we demonstrate an important role for Nod2 in murine skin wound healing. Cutaneous Nod2 is induced in key wound cell types in response to injury. In the absence of Nod2, mice display a substantial delay in acute wound repair associated with epithelial and inflammatory changes. Specifically, Nod2-null mice display altered epidermal migration and proliferation, an initial delay in neutrophil recruitment associated with decreased expression of the chemokine receptor CXCR2, and reduced numbers of alternatively activated macrophages (Ym1(+) cells). Somewhat surprisingly, these Nod2-null phenotypes were associated with little or no expression change in other PRRs, even though compensatory mechanisms have been shown to exist. In this study we show that healing in TLR2-null mice was essentially normal. These findings reveal a novel intrinsic role for Nod2 in cutaneous wound repair in addition to its role in recognizing invading pathogens.


Subject(s)
Dermatitis/metabolism , Keratinocytes/metabolism , Nod2 Signaling Adaptor Protein/deficiency , Skin/metabolism , Wound Healing , Animals , Cell Movement , Cell Proliferation , Cells, Cultured , Dermatitis/genetics , Dermatitis/immunology , Dermatitis/pathology , Female , Genotype , Keratinocytes/immunology , Keratinocytes/pathology , Macrophage Activation , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration , Neutrophils/immunology , Neutrophils/metabolism , Nod2 Signaling Adaptor Protein/genetics , Phenotype , Receptors, Interleukin-8B/metabolism , Skin/immunology , Skin/injuries , Skin/pathology , Time Factors , Toll-Like Receptor 2/deficiency , Toll-Like Receptor 2/genetics
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