LL-37

LL-37 is the only human cathelicidin antimicrobial peptide, a 37-amino acid alpha-helical peptide derived from the C-terminal cleavage of the hCAP18 precursor protein. It is produced by neutrophils, macrophages, epithelial cells, and other cell types as part of the innate immune defense system. LL-37 was first isolated and characterized in the late 1990s and has since become one of the most extensively studied host defense peptides in innate immunology research. The peptide derives its name from the two N-terminal leucine residues (“LL”) and its 37-amino acid length. LL-37 has broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria, fungi, and enveloped viruses. Beyond direct antimicrobial activity, LL-37 functions as an immunomodulatory peptide, influencing chemotaxis, cytokine production, angiogenesis, and wound biology. Its expression is regulated by vitamin D signaling through the VDR/RXR response element in the CAMP gene promoter.

LL-37 has been investigated for its dual antimicrobial and immunomodulatory mechanisms. As an amphipathic alpha-helical peptide, LL-37 inserts into bacterial membranes through electrostatic interactions with anionic lipopolysaccharides (gram-negative) or lipoteichoic acids (gram-positive), forming pores or disrupting membrane integrity. Researchers observed that LL-37 is also effective against biofilms, disrupting the extracellular polymeric matrix and preventing biofilm formation at sub-bactericidal concentrations. Beyond direct antimicrobial activity, LL-37 has been investigated for its immunomodulatory functions: it acts as a chemoattractant for neutrophils, monocytes, and T cells through FPR2/ALX receptor activation; modulates TLR signaling by binding and neutralizing LPS and lipoteichoic acid; and influences dendritic cell differentiation and macrophage polarization. Studies suggest that LL-37 also promotes angiogenesis through VEGF-independent pathways and stimulates keratinocyte migration in wound models.

Antimicrobial Activity

Dürr et al. (2006) reviewed LL-37’s antimicrobial spectrum and membrane-disrupting mechanism, characterizing its activity against a broad range of pathogens and its selectivity for microbial versus mammalian membranes [1].

Biofilm Disruption

Overhage et al. (2008) investigated LL-37’s anti-biofilm properties against Pseudomonas aeruginosa. Researchers observed that LL-37 at sub-inhibitory concentrations reduced biofilm formation, stimulated bacterial motility, and downregulated biofilm-related genes [2].

Immunomodulation

Vandamme et al. (2012) reviewed LL-37’s immunomodulatory functions, describing its effects on chemotaxis, cytokine modulation, TLR signaling, and adaptive immune cell regulation beyond its direct antimicrobial activity [3].