LL-37

LL-37 is the sole human cathelicidin antimicrobial peptide — the C-terminal 37 amino acid fragment of the hCAP18 precursor protein (encoded by the CAMP gene), released by proteinase 3 cleavage from neutrophil granules upon degranulation and by kallikreins (KLK5, KLK7) in skin. Produced by neutrophils, macrophages, mast cells, NK cells, and epithelial cells of skin, lung, and intestine, LL-37 functions both as a direct antimicrobial agent and as a multifunctional immunomodulatory signalling peptide.

LL-37 expression is strongly induced by 1,25-dihydroxyvitamin D3 through vitamin D response elements in the CAMP gene promoter — one of the mechanisms connecting vitamin D status to innate immune capacity. Toll-like receptor activation by bacterial PAMPs (LPS via TLR4, lipoteichoic acid via TLR2, flagellin via TLR5) also induces LL-37 expression through NFkB and IRF3 signalling, providing a feed-forward amplification of the innate immune response: bacterial recognition drives production of the peptide that directly kills bacteria.

The antimicrobial mechanism involves direct bacterial membrane disruption. LL-37 adopts an amphipathic alpha-helical conformation in lipid environments — a helix with hydrophobic residues concentrated on one face and cationic Arg and Lys residues on the other. This amphipathic helix inserts into the negatively charged outer membranes of bacteria (rich in phosphatidylglycerol, cardiolipin, and LPS), disrupting membrane integrity through toroidal pore formation or carpet-model solubilisation. Selectivity for bacterial over mammalian membranes is conferred by membrane charge: bacterial outer leaflets are anionic and attract cationic LL-37, while mammalian outer leaflets are predominantly zwitterionic (phosphatidylcholine, sphingomyelin) and resist LL-37 insertion at concentrations below approximately 10-20 microM.

LL-37 interacts with multiple cell-surface receptors to produce immunomodulatory effects beyond direct killing. FPRL1 (FPR2/ALX, Gi-coupled GPCR) activation promotes chemotaxis of neutrophils, monocytes, and T cells. P2X7 receptor activation at higher concentrations triggers NLRP3 inflammasome assembly and IL-1beta processing. EGFR transactivation in keratinocytes drives proliferation and migration through MAPK/ERK signalling. Direct binding to extracellular double-stranded DNA and RNA enables LL-37 to deliver nucleic acids to endosomal TLR7, TLR8, and TLR9, amplifying innate immune nucleic acid sensing.

LL-37 adopts distinct roles at wound sites: it is chemotactic for keratinocytes, promotes re-epithelialisation through EGFR signalling, stimulates angiogenesis through VEGF induction, and modulates macrophage polarisation from M1 pro-inflammatory to M2 pro-resolving phenotypes during the resolution phase. These wound healing biology connections make LL-37 research complementary to BPC-157, TB-500, and GHK-Cu studies — addressing antimicrobial and immune cell coordination aspects of tissue repair that the other compounds do not cover.