LL-37 is the only human cathelicidin — an antimicrobial peptide that the body makes itself, mainly in white blood cells (granulocytes) and in the skin. The name comes from its structure: 37 amino acids, the first two of which are leucine (L). LL-37 kills bacteria and inhibits biofilm formation, but its more important role is signalling: the peptide acts as an alarm for innate immunity. That same alarm has a dark side — LL-37 can bind the body's own cellular DNA and “convince” the immune system that it is foreign material, which is considered one of the mechanisms driving psoriasis, lupus and rosacea. Human data consist mainly of observations of levels in blood and tissue, plus a few randomised trials in which the peptide was applied topically to chronic wounds. There are no studies of systemic administration to healthy people. This review explains in plain terms what LL-37 is, how it works and why it is a compound with an unusually double-edged profile.
What LL-37 is
Cathelicidins are a family of defence peptides found in many mammals. Humans have only one. In 1996 the group of Gudmundsson and Agerberth described the human gene FALL39 (today CAMP) — a compact gene with four exons, the first three of which code for the signal part and the so-called cathelin domain, while the fourth codes for the antibacterial peptide itself. The authors established that it is the only gene of the cathelin family in the human genome, located the protein in granulocytes and isolated the mature peptide from them, determining its structure as LL-37. Mature LL-37 turned out to be potently antibacterial. It is produced by cleavage from a larger precursor protein (hCAP18) — which is why studies of blood levels often measure hCAP18 itself.
How it works — it kills, but above all it raises the alarm
LL-37 is a cationic (positively charged) defence peptide. In studies with bacteria it acts in two ways. First, at high concentrations it inhibits microbial growth — in the work of Overhage et al. (2008) the minimum inhibitory concentration for Pseudomonas aeruginosa was 64 µg/ml, which the authors plainly called “weak antimicrobial activity”. Second — and this is the more interesting part — already at 0.5 µg/ml, a concentration more than a hundred times lower, it potently inhibited the formation of biofilm (the slimy layer in which bacteria shelter from antibiotics) and disrupted biofilm that already existed. The mechanism was not killing: the peptide reduced bacterial attachment to surfaces, stimulated their motility and disturbed two bacterial “communication” systems (Las and Rhl). In parallel, LL-37 acts on the host's immune cells — and this is where its second, troublesome nature begins.
Structure and origin
LL-37 consists of 37 amino acids cleaved from the end of the protein hCAP18, encoded by the CAMP gene. The gene carries binding sites for acute-phase factors, and the authors who described it suggested a role for interleukin-6 in its regulation — meaning that production rises during inflammation. The peptide sold and used in laboratories is synthetic; the natural one is found in granulocytes and, in the skin — as shown in rosacea — in the form of various fragments, depending on which enzymes have cut it. This matters: “LL-37” in a test tube is a single molecule, whereas “cathelicidin in the skin” is a mixture of forms with different actions.
An autoantigen — psoriasis, lupus, rosacea
The strongest part of the LL-37 literature concerns not its benefits but its harms. In a 2007 paper in Nature, the group of Lande and Gilliet showed that plasmacytoid dendritic cells (specialised alarm cells) normally do not react to the DNA of the body's own cells — but LL-37 binds that DNA into compact aggregates that enter the cell and trigger the receptor TLR9, which in turn drives production of type I interferon. In other words, the peptide turns harmless self-DNA into a strong inflammatory stimulus. The authors regarded this as a mechanism for breaking tolerance to self-DNA and driving psoriasis. In 2014 the same group showed that two-thirds of patients with moderate-to-severe plaque psoriasis carry T lymphocytes that recognise LL-37 as an antigen; these cells produced interferon-γ and Th17 cytokines, infiltrated skin lesions, and their number in the blood correlated with disease activity. The review by Kahlenberg and Kaplan (2013) gathers evidence for a role of LL-37 also in systemic lupus, rheumatoid arthritis and atherosclerosis. In rosacea, Yamasaki et al. (2007) found abnormally high levels of cathelicidin in atypically processed forms in the facial skin of patients, and injecting those forms into mice produced skin inflammation; in mice lacking the cathelicidin gene the effect disappeared.
Human data — blood levels and topically treated wounds
The first group of data is observation of levels. Gombart et al. (2009), in a nested case-control study among 10,044 people starting haemodialysis, compared 81 patients who died of infection within a year with 198 who survived: the baseline level of hCAP18 was lower in those who died (539 versus 650 ng/ml), and people in the lowest tertile had, after adjustment, 3.7 times higher odds of death from infection. Such studies say that a low level of one's own cathelicidin accompanies worse outcomes — they do not say that giving the peptide would improve them.
The second group is randomised trials in which synthetic LL-37 was applied topically to chronic wounds. Grönberg et al. (2014) reported the first-in-man trial: 34 people with hard-to-heal venous leg ulcers, who after a three-week run-in on placebo were randomly assigned for four weeks to LL-37 at three concentrations (0.5, 1.6 or 3.2 mg/ml) or placebo. The two lower concentrations clearly accelerated healing (healing rate constants about six and three times higher than on placebo; ulcer area reduced by 68% and 50%), while the highest did not differ from placebo. The manufacturer then ran the phase IIb HEAL LL-37 trial (Mahlapuu et al., 2021): 148 patients, the two lower concentrations and placebo, all alongside compression therapy. In the whole population no significant difference in healing was found between LL-37 and placebo; only a post hoc analysis pointed to a benefit in patients with large wounds (at least 10 cm²). The drug was well tolerated. A third trial, Miranda et al. (2023, Jakarta), tested an LL-37 cream on diabetic foot ulcers with mild infection: the granulation index rose faster in the LL-37 group at every measurement point, but levels of inflammatory cytokines and bacterial counts in the wound did not differ from placebo.
Safety and the limits of the evidence
In the three trials of topical application to wounds no safety problems were reported — but that concerns small doses applied to the skin for a few weeks. We found no study of subcutaneous or intravenous administration to healthy people, so there are no data on what happens to the immune system after systemic administration of LL-37. Yet the mechanism from Lande's papers is precisely systemic: the peptide bound to self-DNA triggers interferon, and T lymphocytes that recognise LL-37 circulate in the blood of psoriasis patients. This is reasoning from mechanism, not a clinical trial result — but in the case of LL-37 the mechanism is documented in humans, not only in mice. Added to this is the observation from Grönberg's trial that the highest concentration worked no better than placebo: “more” did not mean “more effective”. The limits of the evidence: the clinical trials concern wounds only, the one large trial was negative, some were funded by the manufacturer, and many properties attributed to LL-37 online (antiviral and antifungal action, “sealing the gut”) have no support in human studies. We deliberately give no methods of use and no doses.
The wider context — defence peptides and immunomodulators
LL-37 belongs to the antimicrobial peptides — molecules of innate immunity that in humans also include the defensins. It differs from the “immunomodulating” peptides in our encyclopaedia in that it does not so much strengthen a response as unleash it, including against the body's own tissues. For comparison: thymosin alpha-1 stimulates dendritic cells through TLR receptors in response to microbes and has been through large clinical trials, while the tripeptide KPV acts as an anti-inflammatory in animal models. LL-37 sits at the opposite end of that axis — it is a pro-inflammatory stimulus whose excess is itself a disease.
Summary
LL-37 is the only human cathelicidin: a 37-amino-acid peptide cleaved from the protein hCAP18, produced in granulocytes and in the skin. In the test tube it kills bacteria weakly but inhibits biofilm effectively and acts strongly on immune cells. Its best-documented role in humans is that of an autoantigen: it binds self-DNA and triggers interferon, T lymphocytes that recognise LL-37 circulate in most psoriasis patients, and excess cathelicidin in the skin is a hallmark of rosacea. Randomised trials exist only for topical application to chronic wounds — a small 2014 trial was encouraging, a larger 2021 trial showed no difference from placebo. There are no studies of systemic administration to healthy people. The state of the evidence: strong basic biology, weak and conflicting clinical data, and a documented mechanism of autoimmunity that calls for exceptional caution with this compound.
Sources
- 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 and Regeneration. 2021;29(6):938–950. PMID: 34687253. DOI: 10.1111/wrr.12977. pubmed.ncbi.nlm.nih.gov/34687253
- Grönberg A, Mahlapuu M, Ståhle M, et al. 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 and Regeneration. 2014;22(5):613–621. PMID: 25041740. DOI: 10.1111/wrr.12211. pubmed.ncbi.nlm.nih.gov/25041740
- Miranda E, Bramono K, Yunir E, et al. Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Archives of Dermatological Research. 2023;315(9):2623–2633. PMID: 37480520. DOI: 10.1007/s00403-023-02657-8. pubmed.ncbi.nlm.nih.gov/37480520
- Lande R, Botti E, Jandus C, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nature Communications. 2014;5:5621. PMID: 25470744. DOI: 10.1038/ncomms6621. pubmed.ncbi.nlm.nih.gov/25470744
- Gombart AF, Bhan I, Borregaard N, et al. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clinical Infectious Diseases. 2009;48(4):418–424. PMID: 19133797. DOI: 10.1086/596314. pubmed.ncbi.nlm.nih.gov/19133797
- Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564–569. PMID: 17873860. DOI: 10.1038/nature06116. pubmed.ncbi.nlm.nih.gov/17873860
- Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nature Medicine. 2007;13(8):975–980. PMID: 17676051. DOI: 10.1038/nm1616. pubmed.ncbi.nlm.nih.gov/17676051
- Overhage J, Campisano A, Bains M, et al. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infection and Immunity. 2008;76(9):4176–4182. PMID: 18591225. DOI: 10.1128/IAI.00318-08. pubmed.ncbi.nlm.nih.gov/18591225
- Gudmundsson GH, Agerberth B, Odeberg J, et al. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. European Journal of Biochemistry. 1996;238(2):325–332. PMID: 8681941. DOI: 10.1111/j.1432-1033.1996.0325z.x. pubmed.ncbi.nlm.nih.gov/8681941
- Kahlenberg JM, Kaplan MJ Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. Journal of Immunology. 2013;191(10):4895–4901. PMID: 24185823. DOI: 10.4049/jimmunol.1302005. pubmed.ncbi.nlm.nih.gov/24185823
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.