LL-37

Mechanism of action

LL-37 is the sole human representative of the cathelicidin family of antimicrobial peptides. The mature 37-amino-acid peptide (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) is cleaved from its 18 kDa precursor hCAP-18 by serine proteases including kallikrein 5 and 7 at skin surfaces, and by proteinase 3 in neutrophils. The name 'LL-37' derives from the two N-terminal leucines and the 37-residue length. In solution, LL-37 adopts a predominantly disordered conformation but rapidly forms an amphipathic alpha-helix in the presence of lipid membranes or at physiological ionic strengths at wound surfaces. This conformational shift is central to its antimicrobial mechanism: the helical face positions positively charged lysine and arginine residues toward anionic microbial membrane lipids (phosphatidylglycerol, lipopolysaccharide headgroups), enabling electrostatic docking followed by membrane insertion and disruption. Models of membrane destabilisation include the carpet mechanism (parallel insertion of multiple peptides leading to membrane solubilisation) and toroidal-pore formation. The net result is loss of microbial membrane integrity, ATP leakage, and rapid bacterial death at concentrations in the low-micromolar range. Beyond direct killing, LL-37 functions as a host signalling molecule of considerable potency. It is a ligand for formyl peptide receptor 2 (FPR2/ALX) on neutrophils, monocytes, and macrophages, triggering chemotaxis, degranulation, and cytokine release. On keratinocytes, LL-37 transactivates the epidermal growth factor receptor (EGFR) through ADAM-10/17-mediated shedding of HB-EGF, driving proliferation and migration essential for re-epithelialisation. In endothelial cells, FPRL1 engagement and intracellular signalling downstream promote tube formation and angiogenesis, as characterised by Koczulla and colleagues (J Clin Invest 2003). The dual-edged nature of LL-37 becomes apparent in skin disease. Under normal conditions, LL-37 concentrations at epithelial surfaces are low and tightly regulated by protease-mediated degradation. In psoriasis, however, LL-37 released in excess from activated keratinocytes and neutrophils forms complexes with self-DNA and self-RNA. These complexes are internalised by plasmacytoid dendritic cells via endosomal Toll-like receptor 7 and 9, triggering massive IFN-α release that sustains the psoriatic inflammatory loop — a mechanism elegantly characterised by Lande, Gilliet, and colleagues (Nature 2007). In rosacea, LL-37 produced by serine-protease-activated skin is implicated in driving the angiogenic and inflammatory components of the condition. Thus, LL-37 is both an essential defence molecule and a potential pathogenic driver when dysregulated.

LL-37 forms complexes with extracellular self-DNA in psoriatic skin, enabling these complexes to penetrate plasmacytoid dendritic cells and activate TLR9, triggering massive IFN-α release that sustains the psoriatic autoinflammatory cycle (Lande et al., Nature 2007). This mechanistic discovery transformed understanding of LL-37 from a simple host-defence antibiotic to a pivotal link between keratinocyte-derived antimicrobial peptides and autoinflammatory disease.

— Notable finding

Research history

The cathelicidin gene family was defined in the early 1990s across multiple vertebrate species. The human cathelicidin gene CAMP encodes the precursor protein hCAP-18, which was first identified in human neutrophils by Cowland, Johnsen, and Borregaard in 1995. The mature LL-37 peptide derived from hCAP-18 cleavage was characterised and its antimicrobial activity described by Agerberth and colleagues in 1995, and separately by Gudmundsson and colleagues in 1996. Unlike many species that carry multiple cathelicidin genes, humans carry only one — CAMP — making LL-37 the single human cathelicidin. This evolutionary bottleneck has driven considerable interest in understanding how one peptide can serve such diverse functions across skin immunity, mucosal defence, wound repair, and inflammatory regulation. Seminal work in the early 2000s expanded the LL-37 pharmacology considerably. Heilborn and colleagues (J Invest Dermatol 2003) demonstrated that LL-37 expression was markedly elevated at the wound edge and correlated with re-epithelialisation rate in chronic skin ulcers, and that topical LL-37 accelerated wound closure in animal models. Koczulla and colleagues (J Clin Invest 2003) characterised the pro-angiogenic activity of LL-37 using endothelial tube-formation assays and chick chorioallantoic membrane models, establishing a mechanism beyond simple antimicrobial action. The psoriasis connection emerged from Lande and Gilliet's groups and was published in Nature (2007), profoundly changing understanding of LL-37 from a simple antimicrobial to a central orchestrator of autoinflammatory disease when produced in excess. Subsequent work has implicated LL-37–DNA complexes in lupus and other interferonopathies. In respiratory medicine, LL-37 has been investigated in the context of COVID-19 and vitamin D, since vitamin D signalling via VDR upregulates CAMP gene expression. This link has driven research into whether vitamin D supplementation could bolster LL-37-mediated innate immunity against respiratory pathogens.

Summarised studies

Safety profile

LL-37 presents a substantially more complex safety profile than most research peptides, primarily because it is a potent biological mediator with established pathogenic roles at elevated concentrations. At the concentrations present in normal human tissues (estimated 1–5 µg/mL in sweat and wound fluid, lower in plasma), LL-37 is well tolerated and is essential for mucosal and cutaneous defence. The therapeutic index of exogenously administered LL-37 is less well characterised. In animal studies, subcutaneous and topical delivery has generally been tolerated, but systemic intravenous administration at high doses has been associated with cardiovascular effects attributable to the peptide's membrane-active properties on mammalian cell membranes — selectivity for prokaryotic versus eukaryotic membranes is not absolute. The inflammatory amplification capacity of LL-37 is the most practically relevant safety consideration in research contexts. In individuals with predisposing conditions (atopic diathesis, psoriasis, rosacea), supraphysiological LL-37 concentrations — even topically applied — could theoretically exacerbate skin disease by activating the TLR7/9-pDC-IFN-α axis. This has not been characterised systematically in controlled research, but the mechanistic basis is well established. A significant practical problem in LL-37 research is adsorption to plastic surfaces. LL-37 is highly cationic and binds avidly to standard polystyrene and polypropylene labware, leading to substantial and unpredictable losses of effective concentration. Studies that do not account for adsorption losses may report effective concentrations that are considerably lower than nominal. Low-binding tubes and plates, and addition of carrier protein (BSA at 0.1–0.01%) in non-cellular assays, are recommended in the research literature. Serum and tissue proteins bind LL-37 extensively. Alpha-2-macroglobulin, LDL, and glycosaminoglycans (notably heparan sulphate) all sequester LL-37 and reduce its free concentration, further complicating dose interpretation in cell-culture media containing foetal bovine serum. This protein-binding effect also means plasma half-life measured in vivo may not reflect biologically active concentration at tissue sites.

UK regulatory status

LL-37 is not authorised as a medicine by the UK Medicines and Healthcare products Regulatory Agency (MHRA). There is no marketing-authorisation application for LL-37 on record in the UK or European Medicines Agency databases as a standalone pharmaceutical. LL-37 is not included on the World Anti-Doping Agency (WADA) Prohibited List as of the 2025 iteration. It does not have anabolic, lipolytic, or growth-promoting properties that would place it within the classes of peptides most commonly targeted by WADA (S0, S1, S2). Athletes and researchers in competitive-sport contexts should nevertheless verify the current list, as WADA periodically updates categories. In the United Kingdom, possession of LL-37 for genuine in-vitro laboratory research is unrestricted. It is not a scheduled substance under the Misuse of Drugs Act 1971. Supply for human therapeutic administration or promotion of such use would require MHRA authorisation. No enforcement actions against LL-37 specifically have been publicly reported by the MHRA.

Frequently asked questions