A 37-amino-acid peptide and the only cathelicidin antimicrobial peptide in humans. The primary effector molecule of the innate immune system's first line of defense against bacterial, viral, and fungal pathogens. Also modulates adaptive immunity, wound healing, and inflammation.
LL-37 (named for its two N-terminal leucines and 37-residue length) is the only member of the cathelicidin antimicrobial peptide family in humans. It is produced by neutrophils, macrophages, and epithelial cells of the skin, gut, and respiratory tract as a first-line defense against microbial invasion.
LL-37 is cleaved from its precursor protein hCAP-18 (human cationic antimicrobial protein, 18 kDa) by proteinase 3 in neutrophils or by kallikreins in skin. Its expression is upregulated by vitamin D — which is why vitamin D deficiency is associated with increased susceptibility to infections like tuberculosis.
LL-37 adopts an amphipathic α-helical structure upon contact with bacterial membranes. Like melittin, its cationic charge (+6) attracts it to anionic bacterial membranes, and its hydrophobic face inserts into the lipid bilayer. However, LL-37 has better selectivity for bacterial vs human membranes than melittin, making it less toxic to host cells. Beyond direct killing, LL-37 signals through formyl peptide receptor-like 1 (FPRL1) and P2X7 receptors to recruit and activate immune cells.
| Pathway | Effect | Significance |
|---|---|---|
| Membrane disruption | Amphipathic helix inserts into bacterial membranes causing lysis | Broad-spectrum activity against Gram+, Gram−, fungi, and some viruses |
| Chemotaxis | Activates FPRL1 on neutrophils, monocytes, and T-cells | Recruits immune cells to infection sites |
| LPS neutralization | Binds and neutralizes bacterial endotoxin | Prevents septic shock signaling through TLR4 |
| Wound healing | Promotes keratinocyte migration and angiogenesis | Accelerates epithelial barrier repair |
| Vitamin D regulation | LL-37 gene (CAMP) is transcriptionally activated by vitamin D receptor | Explains the vitamin D-infection susceptibility connection |
| Study | Design | Findings | Level |
|---|---|---|---|
| Genetic studies | Human cohorts | LL-37 deficiency (Kostmann syndrome, specific granule deficiency) causes severe recurrent infections. Confirms essential role in immunity. | Level I (genetic) |
| Vitamin D connection | Observational + mechanistic | Vitamin D supplementation increases LL-37 expression. Low vitamin D → low LL-37 → increased TB susceptibility. | Level I-II |
| Wound healing | Preclinical + clinical pilot | Topical LL-37 promotes chronic wound healing (diabetic ulcers). Phase I/II studies ongoing. | Level II |
| Anti-biofilm | In vitro/in vivo | LL-37 disrupts bacterial biofilms, including MRSA and Pseudomonas biofilms | Preclinical |
| COVID-19 | Observational | Low LL-37 levels associated with more severe COVID-19 outcomes. Vitamin D supplementation trials ongoing. | Level II-III |
Endogenous peptide: LL-37 is naturally produced by the body. Exogenous administration mimics a natural defense mechanism.
Hemolysis at high doses: Like all AMPs, LL-37 can damage red blood cells at concentrations above physiological levels.
Pro-inflammatory potential: Excessive LL-37 is implicated in autoimmune conditions (psoriasis, rosacea, lupus) where it forms complexes with self-DNA that activate TLR9.
| Jurisdiction | Status |
|---|---|
| FDA | Not approved as a drug. Clinical trials ongoing for wound healing. |
| Research | One of the most studied AMPs in the world. >5,000 publications. |
| Vitamin D connection | Public health implication: vitamin D supplementation as an indirect way to boost LL-37 levels |