LL-37 (5mg)

LL-37 Research

LL-37 is the only known human cathelicidin antimicrobial peptide, a critical component of the innate immune system. Since its discovery in the mid-1990s, research on LL-37 has expanded dramatically, revealing its multifunctional roles beyond direct antimicrobial activity.

LL-37 derives its name from its 37-amino acid sequence beginning with two leucine residues. It is cleaved from the C-terminal end of the human cathelicidin protein hCAP18, which is primarily expressed in neutrophils, epithelial cells, and keratinocytes. The peptide adopts an α-helical structure in physiological conditions, which is crucial for its interaction with microbial membranes.

Antimicrobial Activity of LL-37

LL-37 exhibits significant antimicrobial properties against a variety of pathogens, including both Gram-positive and Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus¹.

LL-37’s antimicrobial action involves membrane permeabilization and binding to bacterial lipopolysaccharides, which disrupts bacterial cell integrity.  It is effective even in high-salt environments, although some organisms like methicillin-resistant Staphylococcus aureus and Candida albicans show resistance in such conditions¹.

The peptide operates through a “carpet-like” mechanism, where it disrupts bacterial membranes in a detergent-like manner. This peptide can oligomerize and form structures that interact with both zwitterionic and negatively charged membranes, suggesting a versatile mode of action that includes potential pore formation in bacterial membranes².

LL-37 and Immunomodulation

Beyond its antimicrobial role, LL-37 modulates immune responses by inhibiting macrophage activation and reducing inflammatory cytokine production. It has shown potential in protecting against sepsis and enhancing survival in infection models by suppressing pyroptosis and modulating immune cell recruitment³.

These multifunctional properties make LL-37 a promising candidate for therapeutic applications in infectious and inflammatory diseases.

LL-37 and Wound Healing

LL-37 promotes wound healing by enhancing keratinocyte migration and proliferation, which are crucial for re-epithelialization. This process involves changes in actin dynamics and the activation of signaling pathways such as the mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways. These effects are mediated through the transactivation of the epidermal growth factor receptor (EGFR) and the induction of G-protein-coupled receptor expression⁴.

LL-37 is critical for the re-epithelialization of skin wounds. It is produced in high levels in response to injury and is involved in the proliferation and migration of epithelial cells. In chronic wounds, the absence or reduction of LL-37 impairs re-epithelialization, suggesting its essential role in wound closure⁵.

Chemotactic Properties of LL-37

LL-37 is chemotactic for a variety of immune cells, including neutrophils, monocytes, T cells, and mast cells. It utilizes the formyl peptide receptor-like 1 (FPRL1) to attract neutrophils, monocytes, and T cells, enhancing their recruitment to sites of microbial invasion⁶.

LL-37 induces chemotaxis in mast cells through a Gi protein-phospholipase C signaling pathway, independent of FPRL1⁷. It also acts as a chemoattractant for eosinophils and neutrophils via formyl-peptide receptors, suggesting its involvement in inflammatory lung diseases⁸.

References

1. Turner, J., Cho, Y., Dinh, N., Waring, A., & Lehrer, R. (1998). Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils. Antimicrobial Agents and Chemotherapy, 42, 2206 – 2214. https://doi.org/10.1128/AAC.42.9.2206.
2. Oren, Z., Lerman, J., Gudmundsson, G., Agerberth, B., & Shai, Y. (1999). Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity.. The Biochemical journal, 341 ( Pt 3), 501-13 . https://doi.org/10.1042/BJ3410501.
3. Hu, Z., Murakami, T., Suzuki, K., Tamura, H., Reich, J., Kuwahara-Arai, K., Iba, T., & Nagaoka, I. (2016). Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice.. International immunology, 28 5, 245-53 . https://doi.org/10.1093/intimm/dxv113.
4. Carretero, M., Escámez, M., García, M., Duarte, B., Holguín, A., Retamosa, L., Jorcano, J., Río, M., & Larcher, F. (2008). In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.. The Journal of investigative dermatology, 128 1, 223-36 . https://doi.org/10.1038/SJ.JID.5701043.
5. Heilborn, J., Nilsson, M., Kratz, G., Weber, G., Sørensen, O., Borregaard, N., & Ståhle-Bäckdahl, M. (2003). The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium.. The Journal of investigative dermatology, 120 3, 379-89 . https://doi.org/10.1046/J.1523-1747.2003.12069.X.
6. Yang, D., Chen, Q., Schmidt, A., Anderson, G., Wang, J., Wooters, J., Oppenheim, J., & Chertov, O. (2000). Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells. The Journal of Experimental Medicine, 192, 1069 – 1074. https://doi.org/10.1084/JEM.192.7.1069.
7. Niyonsaba, F., Iwabuchi, K., Someya, A., Hirata, M., Matsuda, H., Ogawa, H., & Nagaoka, I. (2002). A cathelicidin family of human antibacterial peptide LL‐37 induces mast cell chemotaxis. Immunology, 106. https://doi.org/10.1046/j.1365-2567.2002.01398.x.
8. Tjabringa, G., Ninaber, D., Drijfhout, J., Rabe, K., & Hiemstra, P. (2006). Human Cathelicidin LL-37 Is a Chemoattractant for Eosinophils and Neutrophils That Acts via Formyl-Peptide Receptors. International Archives of Allergy and Immunology, 140, 103 – 112. https://doi.org/10.1159/000092305.