LL-37

LL-37 is the sole cathelicidin antimicrobial peptide in humans, produced primarily in neutrophils, mast cells, epithelial cells, and macrophages. It is generated by proteolytic cleavage of the hCAP18 (18 kDa) precursor protein by proteinase 3 or elastase. The designation "LL-37" refers to the two N-terminal leucines and the 37-amino acid length of the mature peptide. LL-37 is a constitutive component of innate immunity, acting as a first-responder defense against a broad spectrum of pathogens while simultaneously orchestrating inflammatory, wound-healing, and tissue-regenerative responses.

The peptide is endogenously expressed and regulated by immune activation, hypoxia, and vitamin D signaling — the latter making it a mechanistic link between vitamin D status and infection susceptibility. Its expression is notably deficient in chronic venous leg ulcers, providing rationale for topical therapeutic applications.

LL-37's antimicrobial mechanism operates primarily through membrane disruption. The peptide adopts an alpha-helical conformation upon contact with negatively charged bacterial membranes and forms oligomeric channels or dissolves the membrane via a "carpet" mechanism, leading to rapid bacterial lysis. This mechanism is effective against over 38 species of bacteria, 16 fungi, and 16 viruses, including drug-resistant organisms. Because the mechanism targets the physical properties of microbial membranes rather than specific molecular targets, resistance development is substantially slower than with conventional antibiotics.

Beyond direct antimicrobial killing, LL-37 acts as a potent immune modulator. It neutralizes lipopolysaccharide (LPS), preventing TLR4-mediated septic shock. It chemoattracts neutrophils, monocytes, and mast cells to sites of infection; inhibits neutrophil apoptosis, prolonging the innate immune response; and stimulates angiogenesis and keratinocyte migration, promoting wound closure. LL-37 also interacts with Toll-like receptors (TLRs 2, 3, 4, 9) as both an agonist and antagonist depending on context.

The peptide's role in cancer is complex and concentration-dependent, with pro-tumorigenic effects at low concentrations (via receptor tyrosine kinase transactivation) and anti-tumorigenic effects at higher concentrations in certain cancer types.