The Lancet LL-37 and Antimicrobial Peptides: Cathelicidin Research in Skin and Immunity

Lancet Insights | 2026-06-26 | 9 min read

Analysis of LL-37 (cathelicidin) and antimicrobial peptides in skin research, covering direct antimicrobial activity, immune modulation, wound healing, and dermatological applications.

LL-37: Cathelicidin in Skin and Immune Research

The Lancet has covered antimicrobial peptides as important components of innate immunity. LL-37 (cathelicidin) represents one of the most important human antimicrobial peptides, with roles in defence, wound healing, and immune modulation. This analysis examines LL-37 biology and research applications.

Cathelicidin Biology

The Cathelicidin Family

Human cathelicidin (LL-37/hCAP18) is the only human cathelicidin:

Precursor: hCAP18 (human cationic antimicrobial protein 18kDa)

Processing:

  • hCAP18 is stored in neutrophil granules
  • Processed by proteases (including KLK)
  • Active LL-37 released at sites of infection/injury

Structure

LL-37 structure determines its function:

Sequence: LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES-OH

Properties:

  • 37 amino acids (hence LL-37)
  • Amphipathic alpha-helix structure
  • Net positive charge (+6)
  • Hydrophobic face for membrane interaction

Mechanisms of Action

Direct Antimicrobial Activity

LL-37 kills pathogens through membrane disruption:

#### Bacterial Killing

Effective against:

  • Gram-positive: S. aureus, E. faecalis, S. pyogenes
  • Gram-negative: P. aeruginosa, E. coli, K. pneumoniae
  • Antibiotic-resistant strains (MRSA, VRE)

#### Mechanism

LL-37 kills through:

  • **Electrostatic attraction**: Positive charge binds negative bacterial membranes
  • **Membrane insertion**: Hydrophobic face enters lipid bilayer
  • **Pore formation**: Disrupts membrane integrity
  • **Cell lysis**: Loss of membrane potential and contents

#### Anti-fungal Activity

LL-37 has activity against:

  • Candida species
  • Aspergillus species
  • Cryptococcus neoformans

Immunomodulatory Functions

Beyond direct killing:

#### Immune Cell Recruitment

  • Chemoattractant for neutrophils
  • Attracts monocytes and T-cells
  • Promotes mast cell degranulation
  • Enhances wound infiltration

#### Angiogenesis Promotion

  • Stimulates endothelial cell migration
  • Promotes new blood vessel formation
  • Supports tissue repair
  • Works with VEGF

#### Anti-inflammatory Effects

Paradoxically, LL-37 can be anti-inflammatory:

  • Modulates cytokine production
  • Promotes inflammation resolution
  • May have pro-inflammatory effects in some contexts
  • Context-dependent actions

Skin Disease Implications

Psoriasis

LL-37 plays a central role in psoriasis:

#### Overexpression

  • Elevated LL-37 in psoriatic skin
  • Complexes with self-DNA/RNA
  • Triggers plasmacytoid dendritic cells
  • Initiates IFN-α production

#### Therapeutic Implications

  • IL-17/IL-23 inhibitors reduce cathelicidin
  • Targeting cathelicidin processing pathways
  • Novel therapeutic approaches

Rosacea

Cathelicidin fragments drive rosacea:

#### Pathogenesis

  • Excessive cathelicidin in rosacea skin
  • Abnormal processing produces pro-inflammatory fragments
  • TRP channel activation
  • Persistent inflammation and flushing

#### Treatment Implications

  • Some rosacea treatments reduce LL-37
  • Potential for cathelicidin-targeted therapy
  • Understanding processing enzymes

Atopic Dermatitis

LL-37 is often deficient in AD:

#### The "Deficiency" Hypothesis

  • Reduced cathelicidin in AD skin
  • Increased susceptibility to infection
  • Contributes to Staph colonisation
  • Impaired wound healing

#### Therapeutic Approach

  • Topical LL-37 supplementation
  • Vitamin D3 to boost endogenous production
  • Treatment of infections

Research Applications

In Vitro Studies

LL-37 research methods:

  • MIC (minimum inhibitory concentration) testing
  • Bacterial killing assays
  • Cell migration assays
  • Cytokine quantification
  • Angiogenesis assays

In Vivo Research

Animal model approaches:

  • Wound healing models
  • Infection models
  • Skin inflammation models
  • Dosing: 0.1-10 mg/kg topically

Clinical Research

Human applications:

  • Chronic wound healing
  • Atopic dermatitis
  • Impetigo and skin infections
  • Burn wound care

Quality Standards

Purity Requirements

LL-37 research requires:

  • HPLC purity ≥99.5%
  • Mass spectrometry verification
  • Accurate peptide quantification
  • Endotoxin testing (<10 EU/mg)
  • Batch-specific COA documentation

Formulation Considerations

Topical formulation research:

  • Appropriate buffer systems
  • pH considerations
  • Stability in formulations
  • Skin penetration

Other Antimicrobial Peptides

Beta-Defensins

Related antimicrobial peptides:

  • hBD-1, hBD-2, hBD-3
  • Different expression patterns
  • Some overlap with LL-37
  • Research combinations

Synthetic Analogues

Novel AMP development:

  • More potent LL-37 analogues
  • Stabilised sequences
  • Reduced toxicity
  • Enhanced activities

Future Directions

Therapeutic Development

Areas for advancement:

  • Topical formulations
  • Combination with antibiotics
  • Treatment of resistant infections
  • Wound healing applications

Understanding Mechanisms

Research needs:

  • Receptor identification
  • Signalling pathways
  • Context-dependent effects
  • Optimal delivery methods

ZePeptide provides research-grade LL-37 with complete analytical documentation for antimicrobial peptide and skin immunology research.

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