Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota

Mouritzen, Michelle Vang; Petković, Marija; Qvist, Katrine; Poulsen, Steen Seier; Alarico, Susana; Leal, Ermelindo C.; Dalgaard, Louise Torp; Empadinhas, Nuno; Carvalho, Eugénia; Jenssen, Håvard

doi:10.1016/j.omtm.2021.02.008

Cited by 22 publications

(17 citation statements)

References 99 publications

(46 reference statements)

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“…It is unclear exactly what control of wound inflammation might look like. It could be by the use of biomaterial dressings that might modulate the immune system or through the modulation of the skin's own host defence peptides to clear an infection and alter the inflammatory phase [65][66][67][68][69]. It might be as simple as reducing the number of monocytes/macrophages entering the wound by repurposing of drugs, for example the use of anti-integrin antibodies to reduce the macrophage load [70].…”

Section: Discussionmentioning

confidence: 99%

Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds

et al. 2021

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Macrophages play a prominent role in wound healing. In the early stages, they promote inflammation and remove pathogens, wound debris, and cells that have apoptosed. Later in the repair process, they dampen inflammation and secrete factors that regulate the proliferation, differentiation, and migration of keratinocytes, fibroblasts, and endothelial cells, leading to neovascularisation and wound closure. The macrophages that coordinate this repair process are complex: they originate from different sources and have distinct phenotypes with diverse functions that act at various times in the repair process. Macrophages in individuals with diabetes are altered, displaying hyperresponsiveness to inflammatory stimulants and increased secretion of pro-inflammatory cytokines. They also have a reduced ability to phagocytose pathogens and efferocytose cells that have undergone apoptosis. This leads to a reduced capacity to remove pathogens and, as efferocytosis is a trigger for their phenotypic switch, it reduces the number of M2 reparative macrophages in the wound. This can lead to diabetic foot ulcers (DFUs) forming and contributes to their increased risk of not healing and becoming infected, and potentially, amputation. Understanding macrophage dysregulation in DFUs and how these cells might be altered, along with the associated inflammation, will ultimately allow for better therapies that might complement current treatment and increase DFU’s healing rates.

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Section: Discussionmentioning

confidence: 99%

Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds

et al. 2021

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“…In addition, A-hBD-2 (20 µg/mL) decreased the terminal differentiation of keratinocytes, enhanced the mobilization of intracellular calcium ions (Ca 2+ ), and promoted wound healing of full-thickness wounds in a rat model, suggesting that A-hBD-2 may be a promising candidate therapy for chronic wounds [ 26 ]. Similarly, Mouritzen et al have assessed the potential of bovine lactoferricin (LFcinB), a 25-amino acid peptide derived from acidic hydrolysis of bovine lactoferrin (bLf), in diabetic wound healing [ 68 ]. LFcinB promoted keratinocyte migration in vitro and ex vivo at a concentration of 25 µg/mL, and enhanced wound healing in a type 1 diabetic mouse model at both concentrations of 12.5 or 25 µg/wound, applied topically over 10 consecutive days (twice the first 2 days and then once daily) [ 68 ].…”

Section: Endogenous and Synthetic Amps As Promising Therapeutic Agents For Infected Woundsmentioning

confidence: 99%

“…Similarly, Mouritzen et al have assessed the potential of bovine lactoferricin (LFcinB), a 25-amino acid peptide derived from acidic hydrolysis of bovine lactoferrin (bLf), in diabetic wound healing [ 68 ]. LFcinB promoted keratinocyte migration in vitro and ex vivo at a concentration of 25 µg/mL, and enhanced wound healing in a type 1 diabetic mouse model at both concentrations of 12.5 or 25 µg/wound, applied topically over 10 consecutive days (twice the first 2 days and then once daily) [ 68 ]. Moreover, LFcinB had antimicrobial activity against B. pumilus and S. aureus , and increased S. xylosus prevalence, a commensal bacterium of the skin, in the type 1 diabetic mouse model [ 68 ].…”

Section: Endogenous and Synthetic Amps As Promising Therapeutic Agents For Infected Woundsmentioning

confidence: 99%

Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers

2021

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Diabetic foot ulcer (DFU) is a devastating complication, affecting around 15% of diabetic patients and representing a leading cause of non-traumatic amputations. Notably, the risk of mixed bacterial–fungal infection is elevated and highly associated with wound necrosis and poor clinical outcomes. However, it is often underestimated in the literature. Therefore, polymicrobial infection control must be considered for effective management of DFU. It is noteworthy that antimicrobial resistance is constantly rising overtime, therefore increasing the need for new alternatives to antibiotics and antifungals. Antimicrobial peptides (AMPs) are endogenous peptides that are naturally abundant in several organisms, such as bacteria, amphibians and mammals, particularly in the skin. These molecules have shown broad-spectrum antimicrobial activity and some of them even have wound-healing activity, establishing themselves as ideal candidates for treating multi-kingdom infected wounds. Furthermore, the role of AMPs with antifungal activity in wound management is poorly described and deserves further investigation in association with antibacterial agents, such as antibiotics and AMPs with antibacterial activity, or alternatively the application of broad-spectrum antimicrobial agents that target both aerobic and anaerobic bacteria, as well as fungi. Accordingly, the aim of this review is to unravel the molecular mechanisms by which AMPs achieve their dual antimicrobial and wound-healing properties, and to discuss how these are currently being applied as promising therapies against polymicrobial-infected chronic wounds such as DFUs.

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“…Many host defence-inspired peptides are used as topical dermal treatments for wound healing [25], and the list of experimentally verified alternatives peptides is long [24,[120][121][122][123][124]. One of the most widely used peptides for wounds with healing impairments and infections is LL-37 [125][126][127][128][129][130].…”

Section: Immunomodulatory Host Defence-inspired Peptide Wound Treatmentsmentioning

confidence: 99%

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

et al. 2021

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Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds.

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Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota

Cited by 22 publications

References 99 publications

Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds

Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds

Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

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