LL-37

LL-37 is the only member of the cathelicidin family of antimicrobial peptides expressed in humans. Its name reflects its structure: 37 amino acids beginning with two leucine residues at the N-terminus. LL-37 is derived from the precursor protein hCAP18 (human cationic antimicrobial protein of 18 kDa), which is stored in the secondary granules of neutrophils and in the granules of macrophages. Upon activation by infection, tissue injury, or inflammatory stimuli, enzymes including neutrophil elastase and serine proteinase 3 cleave hCAP18 to release the active LL-37 peptide into the surrounding tissue and bloodstream. LL-37 is also produced by epithelial cells in the skin, lungs, gut, and urogenital tract as a first-line defense against pathogen invasion.

LL-37's primary antimicrobial mechanism involves its net positive charge of +6, which allows electrostatic attraction to the negatively charged phospholipid membranes of bacteria. Upon membrane contact, LL-37 adopts a helical conformation and inserts into the lipid bilayer, forming transmembrane pores or disrupting membrane integrity through a carpet-like mechanism, leading to bacterial cell lysis. Structural research published in Scientific Reports documented that LL-37 forms a narrow tetrameric channel with a charged core when interacting with bacterial cell wall mimics. This membrane-disrupting mechanism is broadly effective against Gram-positive bacteria (including Staphylococcus aureus and Enterococcus), Gram-negative bacteria (including Pseudomonas aeruginosa and Escherichia coli), and even some drug-resistant organisms such as MRSA and vancomycin-resistant Enterococcus (VRE).

Beyond direct killing of pathogens, LL-37 is an immunomodulatory molecule with complex bi-directional effects. It can both amplify and resolve inflammatory responses depending on context. LL-37 promotes neutrophil and macrophage recruitment, enhances phagocytosis, triggers dendritic cell maturation (contributing to adaptive immune priming), and stimulates angiogenesis and wound healing. At the same time, LL-37 has been shown to neutralize bacterial lipopolysaccharide (LPS), reducing the runaway inflammatory cascade of septic shock. Research during the COVID-19 pandemic prompted interest in LL-37 as a potential protective factor, with a Frontiers in Immunology review proposing that adequate LL-37 levels might reduce the severity of cytokine storm and microthrombosis through its LPS-neutralizing and immunomodulatory properties. Vitamin D is a well-established inducer of endogenous LL-37 production, which provides one mechanism for vitamin D's immune-protective associations.

The primary barrier to therapeutic LL-37 application is its clinical limitations. Despite strong in vitro antimicrobial and immunomodulatory data, LL-37 faces significant hurdles: it is susceptible to rapid proteolytic degradation in biological fluids, shows cytotoxicity toward mammalian cells at concentrations above its antimicrobial threshold, and is expensive to produce in pharmaceutical quantities. No LL-37 formulation has received regulatory approval as of 2026, and human clinical trials remain in early phases. Research interest is high, with multiple groups pursuing modified analogs with improved stability and selectivity.