LL-37

LL-37 is a human host defence peptide with a wide range of biological functions, including antimicrobial and immunomodulatory properties. ^[1] It is the only known member of the cathelicidin family of peptides expressed in humans and is a small peptide of 37 amino acid residues. ^[2] LL-37 is a C-terminal peptide proteolytically released from the 18 kDa human cathelicidin protein (hCAP18). ^[3]

With a small, simple, amphipathic helical structure, LL-37 interacts with bacterial membranes and can act as a pore-forming toxin directed by the organism against bacterial cells. ^[4] Beyond direct killing, LL-37 acts as an alarmin that helps orchestrate the immune response to infection and can both enhance inflammation to combat infection and limit it to prevent tissue damage, while also promoting angiogenesis and wound healing. ^[4] LL-37 also neutralizes lipopolysaccharide, the pro-inflammatory endotoxin produced by Gram-negative bacteria, and can therefore protect against lethal endotoxemia. ^[5] Cellular production of LL-37 is induced through activation of the CAP-18 gene by vitamin D3, linking vitamin D signaling to antimicrobial peptide expression. ^[5]

LL-37 prevents biofilm establishment by many bacterial pathogens through mechanisms including inhibition of bacterial adhesion, downregulation of biofilm-associated genes, suppression of quorum-sensing pathways, and degradation of the biofilm matrix, though many questions about its in vivo efficacy and safety remain. ^[6] LL-37 stimulates the migration and differentiation of mesenchymal stem cells and induces neovascularization and VEGF expression, and has been studied for bone and periodontium regeneration. ^[7] The role of LL-37 in cancer is double-sided, with overexpression found to promote development of ovarian, lung and breast cancers while suppressing tumorigenesis in colon and gastric cancer, through tissue-specific mechanisms. ^[3]

Because of its broad-spectrum activity against bacteria, viruses, fungi and parasites, LL-37 and its derived peptides are of high significance for developing new generations of antimicrobial agents against multi-drug resistant pathogens. ^[8] LL-37 is dysregulated in inflammatory disease: in psoriatic skin, complexes of self-DNA and LL-37 released from neutrophils (neutrophil extracellular traps) induce Th17 responses that drive inflammation. ^[9] Its context-dependent, pro- and anti-inflammatory nature means LL-37 also contributes to disease, as in rosacea, where the TLR2/LL-37/mTORC1 signaling axis is a core regulatory pathway in innate immunity. ^[10]