LL-37

LL-37 is the only cathelicidin-family antimicrobial peptide produced by humans. It is a 37-amino-acid, alpha-helical, cationic peptide (sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) generated by proteolytic cleavage of the C-terminal domain of the precursor protein. That precursor, human cationic antimicrobial protein of 18 kDa (hCAP-18), is the product of the CAMP gene. hCAP-18 is stored in the specific (secondary) granules of neutrophils and is also produced by epithelial cells, monocytes, and mast cells. Upon exocytosis or epithelial secretion, hCAP-18 is cleaved extracellularly, notably by neutrophil-derived proteinase 3, to release the mature, active LL-37 peptide. The name reflects its first two residues (leucine-leucine) and its 37-residue length (Sorensen et al., Blood. 2001).

Cathelicidins are an evolutionarily conserved class of host-defense peptides found across mammals. Many species carry multiple cathelicidin genes, but humans express only this single form. LL-37 was characterized during the 1990s as researchers mapped the antimicrobial peptide repertoire of human neutrophils and epithelium, building on the earlier discovery of the broader cathelicidin family. It is classified structurally as an amphipathic, membrane-active peptide rather than a classical hormone or growth factor. It functions as part of the innate immune system alongside defensins and other host-defense peptides.

Researchers are interested in LL-37 because of its unusually broad functional repertoire. In addition to direct antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi, and some enveloped viruses, LL-37 acts as an immune-signaling molecule sometimes described as an “alarmin.” It also functions as a chemoattractant for neutrophils, monocytes, and T cells, and as a modulator of wound-healing processes including angiogenesis and re-epithelialization. At dysregulated concentrations, it can also contribute to autoimmune skin and systemic disease. This dual protective and pathogenic profile makes it a heavily studied but mechanistically complex molecule.

1. Direct membrane disruption of microorganisms

As a cationic, amphipathic alpha-helix, LL-37 preferentially binds the anionic phospholipids and lipopolysaccharide (LPS) or lipoteichoic acid found in microbial membranes. It inserts into and permeabilizes the lipid bilayer, causing leakage of cellular contents and microbial death. The same amphipathic structure allows LL-37 to bind and neutralize LPS, dampening downstream Toll-like receptor 4 signaling and endotoxin-driven inflammation.

2. Immunomodulation and chemoattraction

LL-37 acts on host immune cells through several receptors, including formyl-peptide receptor-like 1 (FPRL1/FPR2) and P2X7. Signaling through these receptors suppresses spontaneous neutrophil apoptosis, prolonging neutrophil survival at sites of infection (Nagaoka et al., J Immunol. 2006). LL-37 also chemoattracts neutrophils, monocytes, and T lymphocytes. It can also complex with self-DNA released from damaged or dying cells, and this complex is delivered into endosomal compartments of plasmacytoid dendritic cells. There it triggers Toll-like receptor 9 activation and interferon-alpha production, a mechanism implicated in psoriasis pathogenesis (Lande et al., Nature. 2007).

3. Angiogenesis and re-epithelialization

Separate from its antimicrobial and immune roles, LL-37 has been reported to promote keratinocyte migration and endothelial cell proliferation, and to support angiogenesis. These mechanisms are proposed to underlie its investigation as a topical agent for chronic, hard-to-heal wounds (Nijnik and Hancock, Curr Opin Hematol. 2009).

Cell Studies

In vitro work has established that LL-37 permeabilizes bacterial membranes at low micromolar concentrations and binds and neutralizes LPS. It also modulates keratinocyte and endothelial cell behavior relevant to wound closure. It also damages the plasma membranes of erythrocytes, lymphocytes, and fibroblasts in vitro at concentrations similar to those needed for antimicrobial activity. This indicates a narrow window between microbicidal and cytotoxic effects.

Animal Studies

Cathelicidin-related peptides have been evaluated in murine sepsis models, where administration reduced bacteremia and improved survival, supporting an anti-infective mechanism beyond simple membrane lysis. Rodent wound-healing models have also reported accelerated closure with topical cathelicidin peptide application, consistent with the re-epithelialization mechanism identified in cell-based work.

Human Clinical and Cosmetic Studies

LL-37, as an investigational drug product, has been tested clinically for chronic venous leg ulcers, a population that often fails to heal with standard compression therapy alone. A first-in-man, randomized, placebo-controlled trial in 34 patients used a 3-week placebo run-in followed by a 4-week double-blind treatment phase. Healing rate constants for 0.5 mg/mL and 1.6 mg/mL topical LL-37 were approximately six-fold and three-fold higher than placebo, respectively, with mean ulcer area reduced by 68% and 50%.

No local or systemic safety concerns were reported (Gronberg et al., Wound Repair Regen. 2014). A larger, multicentre Phase IIb trial in 148 patients across Poland and Sweden (the HEAL LL-37 study) did not confirm this benefit in the full study population. Only a post hoc subgroup of patients with large wounds (at least 10 cm² at randomization) showed statistically significant improvement in several healing parameters. The drug remained well tolerated at both doses tested (Mahlapuu et al., Wound Repair Regen. 2021). Neither trial has led to a regulatory approval, and no cosmetic (non-wound) clinical trials of LL-37 were identified in the published literature.

Topical LL-37 has been reported as safe and well tolerated, with no significant local or systemic adverse events. This finding held across both published venous leg ulcer trials at concentrations up to 3.2 mg/mL. Outside these controlled dosing contexts, however, LL-37 has a narrow margin between microbicidal and cytotoxic concentrations. In vitro studies show it can lyse erythrocytes, lymphocytes, and fibroblasts at concentrations similar to those needed for antimicrobial effect.

Elevated endogenous LL-37 has been associated with, and may contribute to, the pathology of psoriasis, rosacea, ulcerative colitis, and chronic periodontitis. Circulating T cells from psoriasis patients can also recognize LL-37 as an autoantigen. A widely cited 2013 review summarized evidence linking LL-37 dysregulation to autoimmune conditions including systemic lupus erythematosus and rheumatoid arthritis in addition to psoriasis (Kahlenberg and Kaplan, J Immunol. 2013). There is no established human dosing, injection, or systemic-administration safety profile for LL-37 outside the topical wound-care trials cited above. It has not been evaluated for oral, subcutaneous, or intravenous research use in humans.

LL-37 is the best-characterized human cathelicidin. It has a solid mechanistic and cell-biology literature describing its membrane-disruptive antimicrobial action, its receptor-mediated immunomodulatory effects, and its proposed roles in wound repair. Animal infection and wound-healing models generally support these mechanisms. Human evidence is more limited and mixed. Topical LL-37 was safe and showed a healing signal in a small first-in-man venous ulcer trial.

However, a larger, better-powered Phase IIb trial failed to replicate this benefit in its full study population, achieving statistical significance only in a post hoc subgroup with larger wounds. No LL-37-based product currently holds regulatory approval for any indication. At the same time, LL-37 is not a purely beneficial molecule.

A substantial and separate body of literature identifies elevated or dysregulated LL-37 as a contributor to autoimmune and inflammatory skin disease. Researchers should treat LL-37 as a peptide with a genuine but incompletely proven therapeutic signal. It has a real safety ceiling defined by its cytotoxic and immunogenic potential, and no established protocol exists for anything beyond topical, wound-directed investigational use in humans.

Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3 (Blood)

LL-37, the only human member of the cathelicidin family of antimicrobial peptides (ScienceDirect)

Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial (Wound Repair and Regeneration)

Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide (Nature)

Little Peptide, Big Effects: The Role of LL-37 in Inflammation and Autoimmune Disease (Journal of Immunology)

Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications (MDPI)

1. Sorensen OE, Follin P, Johnsen AH, et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97(12):3951-3959. doi: 10.1182/blood.v97.12.3951.

2. Nagaoka I, Tamura H, Hirata M. An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2X7. J Immunol. 2006;176(5):3044-3052. doi: 10.4049/jimmunol.176.5.3044.

3. Durr UHN, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758(9):1408-1425. doi: 10.1016/j.bbamem.2006.03.030.

4. Gronberg A, Mahlapuu M, Stahle M, Whately-Smith C, Rollman O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22(5):613-621. doi: 10.1111/wrr.12211.

5. Mahlapuu M, Sidorowicz A, Mikosinski J, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial. Wound Repair Regen. 2021;29(6):938-950. doi: 10.1111/wrr.12977.

6. Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol. 2013;191(10):4895-4901. doi: 10.4049/jimmunol.1302005.

7. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564-569. doi: 10.1038/nature06116.

8. Nijnik A, Hancock REW. The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol. 2009;16(1):41-47. doi: 10.1097/moh.0b013e32831ac517.