LL-37 (Cathelicidin)

LL-37 is a 37-amino-acid cationic antimicrobial peptide derived from the C-terminal domain of the human cathelicidin precursor protein hCAP18 (human cationic antimicrobial protein, 18 kDa). Humans encode only a single cathelicidin gene (CAMP, chromosome 3p21.3), making LL-37 the sole human cathelicidin — in contrast to mice and pigs that express multiple family members. The mature peptide begins with two leucine residues (hence the LL-37 nomenclature) and carries a net charge of +6 at physiological pH, driven by its abundant arginine and lysine residues.

The antimicrobial mechanism involves amphipathic alpha-helix formation upon contact with bacterial membranes. LL-37 is intrinsically disordered in aqueous solution but folds into an amphipathic helix at the hydrophobic-electrostatic interface of bacterial surfaces. Cationic residues electrostatically target negatively charged bacterial membrane components — LPS in gram-negative outer membranes, teichoic acids in gram-positive cell walls — while the hydrophobic helix face inserts into the lipid bilayer. At high local concentrations (achieved during neutrophil degranulation), LL-37 disrupts membrane integrity through toroidal pore formation or carpet-model solubilization, resulting in rapid bacterial cell death. Mammalian membranes, composed predominantly of zwitterionic phosphatidylcholine, escape this electrostatic targeting, providing selectivity.

Beyond direct killing, LL-37 has extensive immunomodulatory functions operating through distinct receptors: it acts as an agonist at formyl peptide receptor 2 (FPR2/ALX) on neutrophils and macrophages, driving chemotaxis and ROS production; it binds and neutralizes LPS, preventing TLR4-mediated septic cytokine storms; and it stimulates epithelial production of IL-8, MCP-1, and IP-10 to recruit additional immune cells. In wound healing, LL-37 activates EGFR on keratinocytes through MMP-dependent HB-EGF shedding, promotes angiogenesis via VEGF-dependent and FPR2-mediated pathways, and stimulates fibroblast migration and collagen deposition. Expression is tightly controlled by vitamin D: the CAMP gene promoter contains a functional vitamin D response element (VDRE), making LL-37 production directly dependent on vitamin D status — a mechanistic link between vitamin D deficiency and increased susceptibility to respiratory infections.

LL-37 was first characterized in 1995 by Agerberth and colleagues, who isolated the human cathelicidin gene (originally named FALL-39) from bone marrow and testis, establishing it as the human orthologue of previously characterized cathelicidins in other mammals. The mature 37-residue peptide was subsequently named LL-37 for its N-terminal di-leucine motif and peptide length.

Over the subsequent three decades, LL-37 has become one of the most extensively studied antimicrobial peptides, with over 2,000 publications examining its roles in innate immunity, wound healing, autoimmune disease, and cancer biology. Clinical interest has focused on chronic wounds — where LL-37 deficiency correlates with impaired healing — and on the vitamin D-LL-37 axis in respiratory infection susceptibility, a relationship intensely studied during the COVID-19 pandemic. A synthetic formulation (ropocamptide) has entered clinical development for chronic wound indications. The peptide's dual antimicrobial-immunomodulatory profile has made it a uniquely versatile research tool at the intersection of infectious disease, immunology, and tissue repair biology.

Store lyophilized LL-37 at -20°C in a tightly sealed, desiccated, light-protected container. The 37-amino-acid peptide is moderately stable; the amphipathic helical structure that forms upon membrane contact makes the lyophilized powder slightly more sensitive to moisture than shorter peptides. Minimize vial-open time in humid environments. Stability under optimal conditions exceeds 18 months.

After reconstitution with bacteriostatic water, LL-37 should be stored at 2–8°C and used within 14–21 days. The peptide's cationic character can promote adsorption to glass and plastic surfaces at low concentrations — for protocols using sub-milligram concentrations, consider adding 0.1% BSA as a carrier protein or using siliconized vials. Protect reconstituted solutions from light. Do not freeze reconstituted solutions; freeze-thaw cycles promote aggregation of the amphipathic peptide.