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Antimicrobial peptides are the skin’s endogenous first-responder system – the layer of innate immune defence that operates continuously at the skin surface, within the follicular environment, and at wound sites, without requiring prior sensitisation or acquired immune memory. But calling them simply “the skin’s natural antibiotics” understates what they do by a considerable margin. AMPs modulate immune cell behaviour, shape the composition of the skin microbiome, contribute to wound healing, neutralise bacterial toxins, and interact with host cell receptors in ways that are completely distinct from their antimicrobial function. They are pleiotropic signalling molecules that also happen to kill bacteria – and at the wrong concentrations, in the wrong processing environment, they can become primary drivers of the chronic inflammatory conditions they were designed to prevent.

Two AMP families dominate skin biology: cathelicidins (with LL-37 as the sole human member) and beta-defensins (hBD-1, hBD-2, hBD-3 as the primary skin-relevant members).

The skin is the largest interface between the human body and the external environment, and it does not rely on the adaptive immune system as its primary line of defence. Adaptive immunity – T cells, B cells, antibody production – takes days to mount a response. The skin cannot wait days. What it has instead is a continuously active molecular defence system capable of responding to pathogen challenge within minutes: antimicrobial peptides produced by keratinocytes, neutrophils, mast cells, sebocytes, and sweat glands, deployed at the skin surface and within the follicular environment before any immune cell has been recruited.

AMPs were identified in skin biology research primarily through their antimicrobial properties – the ability to kill bacteria, fungi, and viruses through direct membrane disruption. That is a real and important function. But research over the past decade has established that characterising AMPs as antibiotics misses the larger part of what they do. In contemporary skin immunology, they are more accurately understood as host defence peptides – molecules at the interface of innate immunity and adaptive immune activation, whose behaviour depends as much on concentration, local pH, protease processing environment, and inflammatory context as on their intrinsic molecular properties. ^[3]

Structure and the cationic mechanism

All skin-relevant AMPs share a common structural feature: they are cationic – carrying a net positive electrical charge – and amphipathic, meaning they have both hydrophilic and hydrophobic regions within the same molecule. This combination is not incidental. It is the physical basis of their primary antimicrobial action.

Bacterial cell membranes carry a net negative surface charge, produced by phosphatidylglycerol, cardiolipin, and lipopolysaccharide components. Mammalian cell membranes are comparatively neutral, with cholesterol and zwitterionic phospholipids dominating the outer leaflet. AMPs exploit this charge difference: electrostatic attraction draws the cationic peptide toward the negatively charged bacterial surface, where the amphipathic structure allows the molecule to insert into the membrane and disrupt its integrity through pore formation, membrane thinning, or carpet-model solubilisation. The selectivity for bacterial over mammalian membranes is not absolute – at sufficiently high concentrations, AMPs will disrupt mammalian cell membranes too – but under physiological conditions, the charge differential provides meaningful selectivity. ^[8]

This structural selectivity is also why bacteria cannot easily develop resistance to AMPs through the same mechanisms used against conventional antibiotics. Antibiotic resistance typically involves modifying the target molecule (a specific protein or enzyme) or effluxing the drug before it reaches its target. Restructuring the entire bacterial cell membrane to eliminate its negative charge is metabolically catastrophic for the bacterium – it disrupts every membrane-dependent function simultaneously. Resistance does develop – some pathogens modify their surface charge through lipid A modification or add positively charged polymers to their cell walls – but it is slower, metabolically costly, and generally incomplete compared with conventional antibiotic resistance. ^[8]

Two families, one shared principle

The two AMP families relevant to skin biology operate through the same cationic mechanism but differ substantially in structure, regulation, and the specific biological functions they serve beyond direct antimicrobial activity.

Cathelicidins are produced as inactive precursor proteins (pro-cathelicidins) that require extracellular protease cleavage for activation. In human skin, the sole cathelicidin is hCAP18, which is cleaved primarily by the serine protease KLK5 to generate the active 37 amino acid peptide LL-37. This processing dependency means that LL-37’s activity is not simply a function of how much hCAP18 is produced – it is equally determined by the protease environment at the skin surface. The pH, temperature, LEKTI inhibitor activity, and competing substrate availability all modulate the KLK5 cleavage rate and therefore the local LL-37 concentration. LL-37 is the focus of the LL-37 child entity.

Defensins are disulphide bond-stabilised peptides with a characteristic beta-sheet structure. Alpha-defensins are found primarily in neutrophil granules (human neutrophil peptides, HNPs) and paneth cells. Beta-defensins are the predominant defensin class in skin, expressed by keratinocytes and other epithelial cells. The three most clinically relevant in skin biology are hBD-1 (constitutive expression), hBD-2 (inducible), and hBD-3 (inducible, broad-spectrum). Beta-defensins are the focus of the beta-defensin child entity. ^[4]

Beyond antimicrobial: the immunomodulatory functions

This is where the biology becomes genuinely interesting – and where most content on AMPs stops short.

Chemotaxis and immune cell recruitment. LL-37 acts as a chemoattractant for neutrophils, monocytes, and T cells through formyl peptide receptor 2 (FPR2) and CCR2 binding. hBD-2 and hBD-3 are chemotactic for dendritic cells and memory T cells through CCR6 binding. AMPs do not simply kill pathogens at the site of challenge; they actively recruit the cellular immune response to that site. They are the molecular equivalent of a distress signal that simultaneously kills the attacker and calls for reinforcements. ^[1]

LPS and LTA neutralisation. LL-37 binds lipopolysaccharide (LPS) from gram-negative bacteria and lipoteichoic acid (LTA) from gram-positive bacteria with high affinity, neutralising these potent TLR4 and TLR2 agonists before they can trigger full systemic inflammatory activation. This function operates regardless of whether LL-37’s antimicrobial activity is engaged – at sub-bactericidal concentrations, LL-37 can still neutralise substantial quantities of LPS. In the context of skin barrier disruption, where microbial products are penetrating the compromised barrier, this endotoxin-neutralising capacity provides a buffer against uncontrolled TLR-mediated inflammation. ^[11]

Mast cell interaction. LL-37 degranulates mast cells directly through TLR2/JAK2/STAT3 signalling, as characterised by Fan et al. (2025) – a property that is physiologically important in wound healing (mast cell degranulation releases histamine and growth factors that initiate repair) but becomes pathological in rosacea, where excess LL-37 triggers disproportionate mast cell activation producing the flushing, erythema, and inflammatory cascade characteristic of the condition. ^[5]

Wound healing. AMPs are integral to the wound repair process independently of their antimicrobial activity. LL-37 promotes keratinocyte migration, proliferation, and angiogenesis through EGFR transactivation and VEGF upregulation. hBD-3 activates autophagy in keratinocytes – a cellular homeostasis mechanism that clears damaged proteins and organelles and supports the differentiation programme required for barrier reconstruction. These are not secondary effects; they are mechanisms operating in parallel with the antimicrobial function in every wound. ^[9]

NLRP3 inflammasome modulation. Context-dependently, LL-37 can both activate and suppress NLRP3 inflammasome signalling. At physiological concentrations in healthy skin, LL-37 suppresses LPS-driven NLRP3 activation – reducing IL-1β production and inflammatory amplification. At the elevated concentrations seen in rosacea and psoriasis, LL-37 drives NLRP3 activation through a separate mechanism involving mitochondrial reactive oxygen species. The same molecule. Opposite outcomes. Determined entirely by concentration and cellular context. ^[1]

The microbiome-AMP bidirectional circuit

AMPs shape the microbiome. That much is broadly understood – AMPs kill pathogens and selectively spare commensals through tolerance mechanisms those organisms have evolved over millennia of co-habitation. But the relationship is bidirectional in a way that is rarely discussed explicitly: the skin microbiome actively induces AMP production.

Staphylococcus epidermidis is the clearest example. Through TLR2 ligand activity – specifically through its cell wall lipoteichoic acid and lipoproteins – S. epidermidis induces hBD-2 and hBD-3 expression in keratinocytes at concentrations well below those required to trigger overt inflammation. The circuit operates continuously in healthy skin: commensal presence at low, homeostatic levels maintains a baseline hBD-2/hBD-3 tone that preferentially targets pathogens like S. aureus (which has not developed the same tolerance mechanisms) while leaving the commensal population intact. ^[7]

The practical consequence of this circuit is a second explanation for why microbiome dysbiosis increases pathogen vulnerability – beyond simple competition exclusion. A skin microbiome depleted of S. epidermidis diversity does not merely vacate the niche that S. aureus can colonise. It also removes the TLR2 stimulation that was maintaining hBD-2 and hBD-3 tone. The AMP defence degrades alongside the commensal ecosystem that was generating it. ^[12]

Other commensals contribute similarly. Cutibacterium acnes activates TLR2 at physiological concentrations, maintaining a background level of hBD-2 induction at sebaceous sites that contributes to pathogen exclusion in the follicular environment. The commensal community is not merely a passive occupant of the skin surface. It is actively co-managing the host’s innate immune defence.

Vitamin D: the master upstream regulator

Of all the molecules that regulate AMP production, vitamin D has the most direct, best-characterised, and most clinically actionable relationship. The vitamin D receptor (VDR) drives transcription of the CAMP gene – encoding hCAP18, the LL-37 precursor – through a directly confirmed vitamin D response element (VDRE) in the CAMP promoter. At physiologically relevant concentrations of 1,25-dihydroxyvitamin D3, hCAP18 protein expression in keratinocyte models increases approximately 13-fold. VDR activation also drives hBD-2 and hBD-3 expression, though through more complex pathways involving suppression of the IL-17/ NF-κB axis rather than pure direct promoter activation. ^[2]

The implication is clinically significant and underappreciated in aesthetics practice. Vitamin D deficiency – defined as serum 25(OH)D below 50 nmol/L, a threshold that a meaningful proportion of the UK population falls below, particularly through winter – does not merely affect bone metabolism and calcium regulation. It depresses the skin’s AMP production capacity from a single upstream regulatory point, affecting both the cathelicidin and beta-defensin families simultaneously. For clients presenting with recurrent skin infections, persistent barrier fragility, or atopic presentations – any condition where AMP insufficiency is a plausible contributing factor – vitamin D status is a clinically relevant variable. ^[2]

AMPs in context: the condition spectrum

The same AMP molecules behave very differently across different skin conditions – a point that is essential to the clinical context and that competitor content almost universally misses by treating AMPs as uniformly protective.

The pattern here – reduced AMPs in AD, elevated AMPs in rosacea and psoriasis – makes the clinical point precisely: AMPs are not uniformly beneficial, and their management cannot be uniformly “stimulate more AMP production.” The goal is appropriate AMP expression in the appropriate context – controlled by the upstream regulators that ensure the right concentration reaches the right site. ^[11]

AMP decline in ageing

Progressive AMP decline is a genuine ageing biomarker with direct clinical consequences. Three mechanisms converge with age:

Reduced VDR sensitivity. Keratinocyte vitamin D receptor expression and responsiveness decline with chronological age, reducing the vitamin D-driven CAMP and hBD induction that provides baseline AMP tone independent of inflammatory stimulation. ^[3]

Reduced microbiome diversity. The commensal community that drives hBD-2 and hBD-3 via TLR2 signalling becomes less diverse with age – particularly after repeated antibiotic courses, barrier disruption events, and the sebum decline that removes C. acnes from the sebaceous sites where it was contributing to TLR2 stimulation. ^[6]

Reduced keratinocyte differentiation capacity. AMP production is linked to the keratinocyte differentiation programme – cells in the upper stratum spinosum and granulosum are the primary sources of skin-surface LL-37 and beta-defensins. Differentiation capacity declines with age as keratinocyte proliferative function reduces. ^[3]

The clinical consequence is measurable: aged skin shows increased S. aureus colonisation rates, impaired wound healing, and slower resolution of minor infections – all consistent with a progressive AMP deficit. This connects the skin immunology story to the skin ageing story in a way that most ageing-focused content ignores entirely. AMP decline is not just a consequence of ageing – it is a mechanism of the increased vulnerability that makes aged skin clinically distinct from younger skin. ^[6]