LL-37 and Skin Research: Dermal Innate Immunity, Wound Repair Biology and Keratinocyte Mechanisms UK 2026

Research Use Only. LL-37 is not licensed as a dermatological therapeutic in the UK. All content describes preclinical and investigational research biology. Not medical advice.

LL-37 (the C-terminal 37-amino acid peptide of human cathelicidin hCAP-18, sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) is the only cathelicidin found in humans and is constitutively expressed in skin. Beyond its antimicrobial function, LL-37 is a multifunctional host defence peptide with direct roles in keratinocyte biology, wound healing, and inflammatory regulation in skin — making it one of the most physiologically relevant peptides for dermatological research.

LL-37 Expression and Release in Skin

LL-37 is stored as the proform hCAP-18 in secretory granules of keratinocytes and is processed extracellularly by kallikrein-5 (KLK5) and kallikrein-7 (KLK7) serine proteases in the stratum granulosum to release active LL-37. Baseline expression in the epidermis is low in intact skin but is dramatically upregulated by: wounding (TGF-β1, EGF, keratinocyte growth factor, H₂O₂); infection (TLR2/TLR4 ligands — LPS, Pam3CSK4); UV radiation (via Vitamin D3/VDR pathway — the UV-1,25(OH)₂D₃-VDR-CAMP promoter axis is a critical inducer of cathelicidin in sun-exposed skin); and cytokines including IL-6, IL-17, and IFN-γ. CAMP gene (encoding hCAP-18) promoter activity driven by VDR-RXR heterodimer binding to VDRE (vitamin D response element) is the best-characterised transcriptional control mechanism.

Keratinocyte Biology: Migration and Re-Epithelialisation

Re-epithelialisation — the migration of keratinocytes from wound margins across the exposed wound bed — is a critical determinant of wound healing speed. LL-37 acts as a direct keratinocyte chemotactic agent and pro-migratory signal via:

EGFR transactivation: LL-37 at 0.5–5 µM transactivates epidermal growth factor receptor (EGFR) through metalloprotease-dependent HB-EGF (heparin-binding EGF) ectodomain shedding (ADAM10/ADAM17 → HB-EGF → EGFR Tyr-1068 phosphorylation → Ras-MAPK-ERK1/2 + PI3K-Akt). ERK1/2 activation promotes cell cycle G1→S progression (cyclin D1 upregulation), and Akt-mTOR drives protein synthesis for the lamellipodia and cytoskeletal machinery required for directed migration. Keratinocyte scratch wound assay (confluent HaCaT or primary NHEK monolayer, 200 µl pipette tip wound, 0.5–5 µM LL-37, photographic analysis at 0/8/24h, ImageJ wound closure %) quantifies this effect.

FPR2 (formyl peptide receptor 2) chemotaxis: LL-37 is a high-affinity FPR2/ALX agonist (Kd ~200 nM). FPR2 is expressed on keratinocytes and couples to Gi → reduced cAMP → PI3K-Akt-Rac1 → lamellipodia extension. FPR2 antagonist WRW4 (10 µM) blocks LL-37-stimulated keratinocyte migration independently of EGFR, demonstrating dual receptor engagement.

STAT3 phosphorylation: LL-37 activates STAT3 pTyr-705 in keratinocytes through IL-6 trans-signalling amplification and direct non-canonical STAT3 activation. STAT3 drives keratinocyte proliferation (keratin 6/16 upregulation) and wound-responsive gene programmes.

Antimicrobial Defence in Skin: Biofilm and Chronic Wound Context

Chronic wounds (diabetic foot ulcers, venous leg ulcers, pressure ulcers) are characterised by polymicrobial biofilm infection, impaired re-epithelialisation, excessive MMP activity, and reduced LL-37 expression relative to acute wounds. The reduction in LL-37 in chronic wounds correlates with failure to control Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis biofilm formation.

LL-37 disrupts established biofilms (MBEC — minimum biofilm eradication concentration — determined by crystal violet staining in 96-well plate Calgary biofilm device) through: membrane depolarisation (DiSC₃(5) fluorescence assay, inner membrane potential collapse); dispersal-promoting signalling (P. aeruginosa cdi GTPase activation → biofilm dispersal); and reduction of quorum-sensing molecule production (N-acyl homoserine lactone, AHL HPLC-MS quantification from biofilm-conditioned media). The MBEC for LL-37 against S. aureus biofilm is typically 16–64 µg/ml (versus MIC 2–8 µg/ml for planktonic bacteria) — a 4–16-fold biofilm tolerance factor that must be acknowledged in research design.

In vivo chronic wound models: db/db diabetic mouse (leptin receptor deficient, impaired wound healing baseline) or STZ-induced diabetic mouse with full-thickness excisional wounds contaminated with MRSA (10⁶ CFU intradermal, confirmed wound biofilm by confocal FISH/CLSM at day 3). LL-37 topical application (50–200 µg/wound in hydrogel vehicle, daily for 7 days): wound closure rate (digital photography ImageJ), CFU count from wound biopsy homogenate at day 3/7, biofilm FISH/CLSM, and histological healing score.

Anti-Inflammatory Skin Biology

Despite potent pro-inflammatory activities at high concentrations, physiological LL-37 concentrations modulate skin inflammation in a context-dependent manner:

Rosacea and neutrophil recruitment: Rosacea skin contains elevated LL-37 and KLK5, driving aberrant innate immune activation. LL-37 at elevated concentrations (>5 µg/ml) stimulates mast cell degranulation, VEGF-A release (promoting telangiectasia), and recruits neutrophils via CXCL8/IL-8 (through TLR4/NF-κB in keratinocytes). In rosacea research, LL-37 signalling inhibition (FPR2 antagonist, KLK5 inhibitor) is under investigation — distinct from the pro-wound-healing context where LL-37 stimulation is desired. The concentration-dependence (anti-inflammatory at 0.1–1 µg/ml, pro-inflammatory at >5 µg/ml) is a critical study design consideration.

Psoriasis paradox: Psoriasis plaques have markedly elevated LL-37 — but rather than resolving the inflammatory cycle, LL-37 forms complexes with self-DNA released from necrotic keratinocytes, activating plasmacytoid dendritic cell (pDC) TLR9 to produce IFN-α, driving the psoriatic Th17/IL-23 inflammatory loop. This LL-37-DNA-TLR9 axis is research-relevant for understanding innate immune activation in autoimmune skin disease. IMQ (imiquimod) mouse psoriasis model (62.5 mg topical 5% Aldara cream daily × 6 days, PASI-equivalent scoring) quantifies LL-37-TLR9 anti-pDC interventions.

Angiogenesis and Vascular Biology in Wound Healing

Angiogenesis — new capillary formation from existing vessels — is essential for granulation tissue vascularisation and wound healing. LL-37 acts as a direct angiogenic peptide via FPR2 on endothelial cells: HUVEC tube formation (Matrigel assay, tube length/branch point quantification at 6h), HUVEC migration (scratch/Boyden chamber), and endothelial proliferation (BrdU incorporation). LL-37-FPR2-Gi → Rac1-lamellipodia in endothelial cells drives sprouting angiogenesis. In vivo: Matrigel plug assay (Matrigel + LL-37 5–50 µg/plug s.c., 7 days, haemoglobin Drabkin content, CD31/vWF IHC for vessel density). Additionally, LL-37 upregulates VEGF-A production in keratinocytes (qPCR/ELISA conditioned media), providing an indirect angiogenic signal through the most potent classical angiogenic growth factor.

Mast Cell Biology

Mast cells in the dermis express FPR2 and respond to LL-37 with selective degranulation — releasing preformed mediators (histamine, tryptase, TNF-α from granules) and newly synthesised lipid mediators (PGD₂, LTC₄) and cytokines (IL-8, VEGF-A). The mast cell response to LL-37 is distinct from IgE-crosslinking degranulation: it does not involve FcεRI and is blocked by FPR2 antagonist WRW4 but not by the H1-blocker cetirizine used in IgE-dependent responses. Research designs should include: β-hexosaminidase release assay (granule exocytosis quantification, spectrophotometric at 405 nm), LAD2 or HMC-1 mast cell lines, bone marrow-derived mast cells (BMMCs, SCF+IL-3 culture 4–6 weeks), and primary human skin mast cells (collagenase skin digest, MACS CD117+ selection).

Atopic Dermatitis and Skin Barrier Research

Atopic dermatitis (AD) is characterised by skin barrier dysfunction (filaggrin loss, ceramide deficiency) and immune skewing toward Th2/IL-4/IL-13 with paradoxical LL-37 reduction relative to psoriasis — rendering AD skin susceptible to S. aureus colonisation that normal cathelicidin levels would suppress. The Th2/IL-4/IL-13 cytokine environment directly suppresses CAMP gene expression (STAT6-mediated inhibition of VDR-VDRE activity), explaining the LL-37 deficit. MC903 (calcipotriol) mouse AD model (topical 2 nmol daily × 7 days, ear pinna) produces Th2 skin inflammation with LL-37 reduction. LL-37 topical application in MC903 AD model: TEWL (transepidermal water loss, Tewameter), skin hydration (corneometry), S. aureus CFU per cm², histological inflammatory score (H&E: epidermal thickness, eosinophil/mast cell density), and serum IgE.

Summary

LL-37 is a physiologically constitutive skin host defence peptide with multifunctional roles spanning keratinocyte migration (EGFR transactivation, FPR2-Rac1), antimicrobial biofilm disruption (membrane depolarisation, quorum-sensing reduction), angiogenesis (FPR2-endothelial VEGF-A, Matrigel plug), mast cell selective degranulation, and context-dependent inflammatory modulation. In wound healing research, LL-37 promotes re-epithelialisation, vascularisation, and infection control. In chronic wounds, biofilm tolerance and LL-37 deficiency are mechanistic targets. In skin inflammatory disease, the concentration-dependence of LL-37’s inflammatory effects and the TLR9-pDC-IFN-α axis in psoriasis represent distinct research angles requiring carefully designed concentration controls and appropriate disease model selection.