The human body possesses a complex array of defense mechanisms to protect against invading pathogens and maintain overall health. Among these natural defenses is LL-37, a molecule that plays a fundamental role in the body’s protective responses. This peptide contributes to the innate immune system, acting as a broad-spectrum agent against various threats.
What is LL-37?
LL-37 is a small protein segment classified as a cathelicidin antimicrobial peptide. It is the only cathelicidin-derived polypeptide found in humans. This peptide is formed from a larger precursor protein called hCAP18, which is primarily stored in immune cells like neutrophils and in various epithelial cells throughout the body.
The name LL-37 comes from its structure: it begins with two leucine amino acids (“LL”) and is composed of 37 amino acids. This peptide has a net positive charge, allowing it to interact with negatively charged microbial membranes. LL-37 is found in diverse locations, including the skin, lungs, gastrointestinal tract, and in circulating neutrophils and bone marrow cells.
How LL-37 Protects the Body
LL-37’s protective actions stem from its ability to directly combat various microbes, modulate immune responses, and promote tissue repair.
LL-37 exhibits broad-spectrum antimicrobial activity against bacteria, viruses, and fungi. It directly kills or inhibits microbial growth primarily by disrupting their cell membranes. The peptide’s positive charge allows it to bind to the negatively charged surface of bacterial membranes, leading to the formation of pores that compromise cell integrity and cause cell lysis. LL-37 has also been shown to inhibit viruses such as SARS-CoV-2, Zika, and Ebola.
LL-37 also regulates the immune system. It can attract immune cells, such as neutrophils, monocytes, and dendritic cells, to sites of infection or injury, serving as an alarm signal. This peptide also influences inflammatory responses; it can both stimulate and downregulate cytokine production, helping to maintain a balance between pro- and anti-inflammatory signals. LL-37 can also neutralize bacterial components like lipopolysaccharide (LPS), thereby limiting excessive inflammation.
LL-37 contributes to tissue repair and regeneration. It stimulates the proliferation and migration of various cell types involved in wound healing. LL-37 promotes angiogenesis, the formation of new blood vessels, which is important for delivering nutrients and immune cells to damaged tissues.
LL-37’s Involvement in Health Conditions
The balance of LL-37 levels and its activity is important for maintaining health, as both excessive and insufficient amounts can contribute to various health conditions.
Elevated levels of LL-37 are observed in several inflammatory and autoimmune diseases. In conditions like psoriasis, LL-37 is overexpressed in the skin, where it can contribute to the disease’s pathology. In psoriasis, LL-37 can form complexes with self-DNA or RNA, which can then activate immune cells like plasmacytoid dendritic cells to release type I interferons, intensifying the inflammatory cascade. This overexpression can also contribute to the increased risk of cardiovascular disease seen in psoriasis patients by enhancing LDL uptake in macrophages. Similarly, in systemic lupus erythematosus (SLE), increased LL-37 levels are associated with inflammasome activation and elevated production of certain inflammatory cytokines, potentially promoting disease development.
Conversely, a deficiency or impaired function of LL-37 can increase susceptibility to infections. In cystic fibrosis, for example, patients often have compromised innate immunity in the lung, which can be linked to dysfunctional LL-37, leading to frequent bacterial infections. While LL-37 levels can be elevated in the bronchoalveolar lavage fluid of cystic fibrosis patients, indicating its presence, its effectiveness may be hindered or its presence may even stimulate the growth of certain pathogens like Aspergillus fumigatus under specific conditions. Low LL-37 levels in the skin, such as in atopic dermatitis or chronic ulcers, may also explain the increased risk for skin infections in these conditions.
Research and Therapeutic Potential
Ongoing research into LL-37 focuses on understanding its complex mechanisms and harnessing its properties for medical applications. The unique characteristics of this peptide make it an interesting candidate for new therapeutic strategies.
Scientists are exploring the development of LL-37-based therapies to address challenges such as antibiotic resistance. Its broad-spectrum antimicrobial activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), suggests its potential as an alternative to conventional antibiotics. Efforts are underway to create synthetic LL-37-derived peptides that maintain its beneficial properties while potentially improving stability and reducing toxicity to human cells. These modified peptides are being investigated for topical application in treating infected wounds.
The wound healing capabilities of LL-37 are also being studied for therapeutic use. Clinical trials have investigated its effectiveness in enhancing the healing of chronic wounds, such as venous leg ulcers and diabetic ulcers, with some studies showing promising results in reducing wound size and promoting tissue repair. Beyond direct infection and wound healing, LL-37’s immune-modulating effects are being examined for their potential in regulating autoimmune responses, offering insights into new approaches for inflammatory conditions like inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Studying LL-37 continues to deepen the understanding of the innate immune system’s intricate defense mechanisms.