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.
Acute wounds in diabetic patients can adopt and portray the chronicity of the non-healing wounds due to bottom-line complications like the duration of diabetes or vascular disease paired with peripheral neuropathies. Wounds that do not heal naturally within three months are defined as chronic wounds, and often require treatment to heal. Wounds that have healing difficulties are subcategorised into four aetiology categories: venous, pressure, diabetic and arterial insufficient ulcers. Non-healing wounds share a lack of oxygen and nutrient supply and microbial contagion, delaying the wound from healing. Diabetic foot ulcerations occur in about 20% of the diabetic population, being prevalent among the chronic wound aetiologies, like venous and pressure ulcers.
Other inflammatory skin conditions like psoriasis and atopic dermatitis are also characterised by dysregulation of the immune response, attacking healthy skin cells.
Host defence peptides are polycationic peptides exhibiting various antimicrobial activities or prompting the host’s immune responses. These agents are naturally produced by a wide variety of species, ranging from marine organisms to humans. Recent studies propose the dual importance of host defence peptides (HDPs) in the different phases of wound healing. As the first line of defence against pathogenic bacterial infection, HDPs are a critical element in preventing biofilm-associated infections. A decline in sufficiently effective antibiotic treatments due to growing problems with antibiotic resistance may be ameliorated with alternatives to conventional antibiotics like peptides with antimicrobial properties. Aside from bacterial pathogen inactivation by disrupting their cell membranes, host defence peptides also have immunomodulatory properties, due to their ability to stimulate the cross-talk between immune cells promoting cutaneous wound healing in a healthier manner.
Different HDPs share some similarities like the number of amino acid residues being between 10 and 60, a cationic charge of 2–9 and depending on the sequence length, HDPs are classified as long (50–100 amino acids), intermediate (25–50 amino acids) or short (9–24 amino acids). The diverse structure yet positive net charge that they have in common is an important prerequisite for the design of the more stable, synthetic analogues that interact with anionic prokaryotic membranes: lipopolysaccharides (LPS; in Gram-negative bacteria) and teichoic acids (in Gram-positive bacteria). Host defence peptides and their synthetic analogues called peptidomimetics, which contain sequences built by natural and unnatural amino acids. These building blocks determine the signature physiochemical properties, which are the charge (neutral or positive) and the hydrophobicity/hydrophilicity. These in turn contribute to the other level of structural complexity that plays a significant role in the activity: the secondary structures of HDPs. Aside from their known potential for evading infections, an increasing body of evidence has demonstrated that HDPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. The latter activity is referred to as immunomodulatory activity, and multiple studies have presented evidence on this important role in innate and adaptive immune response. Most of the HDP derivatives include a combination of microbicidal action and immunomodulatory functions. The challenges associated with creating a non-immunogenic peptide without the potentially adverse effects observed in natural HDPs may be defeated by the modification of internal sequences or single amino acid substitutions. An example of such peptides is innate defence regulator peptides (IDR peptides). Specific signature structure properties that allow synthetic peptides to exert immunomodulatory properties are yet not well defined in the literature and are quite diverse.
Cationic peptides play a primarily role in maintaining the skin barrier’s integrity and cutaneous tissue restoration during injury. Due to expanding the effects of antimicrobial peptides on bacteria, HDP have been assigned the fundamental biological role in innate immunity. Due to their lack of adaptive immune systems, arthropods and plants rely on their HDPs’ primary defence response. In higher eukaryotes, the levels of the host’s defence peptides patrolling through signalling networks of the immune response are significantly more abundant, as their multifaceted role is more complex.
Skin resident HDPs are crucial participants of each step of the wound healing process: inflammation (neutrophil and macrophage infiltration), wound site regeneration (angiogenesis and re-epithelialization) and remodelling (restoration of tensile strength).
In humans, two main classes of host defence peptides have been identified: defensins and cathelicidins (Figure 1). However, there are also a variety of other small peptides expressed by epithelial cells like Substance P, neurotensin, granulysin, calprotectin, adrenomedullin, MRP8/MRP-14 and RNase A superfamily, which are also important wound inflammatory biomarkers.
Peptides from the defensin family are small peptides that are widely distributed across species, including humans. Human defensins (HDs) are produced in leukocytes and are also secreted by different epithelial cells and mucosal tissues. The mature defensins are described as short (28–42 amino acids length), cationic (net charge +1 to +11), amphipathic peptides with a highly conserved tertiary structure of a triple antiparallel β-sheet fold arrangement accommodating the six cysteine residues connected with three disulphide bridges.
Moreover, depending on the size, location, spatial conformation, and spot where the cysteines lay within the peptide chains, they are categorised as α-defensins, β-defensins and θ-defensins. In humans, only α and β-defensins are present, while structurally different, cyclic θ-defensins have been identified in rhesus macaques.
Additionally, the HDs have antimicrobial activity against various strains of Gram-positive and negative bacteria, fungi and viruses such as the herpes simplex virus.
In humans, there are 6 α-defensins: HNPs1–4 and human α-defensins 5 and 6 (HD5 and HD6). HNPs 1–3 (human neutrophil peptides) differ by single amino acid substitutions and are predominantly produced by neutrophils.
Moreover, β-defensins abundance is tightly governed by transcriptional controls assigned to epithelial and epidermal cells. One representative of the β-defensin family such as human β-defensin 1 (HBD1) is continuously transcribed in skin cells, while the transcription of human β-defensin 2 (HBD2) and human β-defensin 3 (HBD3) as the others is triggered in response to a microbial or pro-inflammatory cytokines presence.
Endogenous cathelicidins are stored at high concentrations as inactive precursors in granules of mammalian neutrophils and mast cells. In contrast to defensins, cathelicidins are predominantly α-helical, amphipathic, cationic (possessing a net
