The LL-37 peptide is a small protein found in humans, a component of the innate immune system. It plays a broad protective role throughout the body, acting as a direct defense mechanism against various foreign invaders. LL-37 is produced by various cells and tissues, signifying its widespread involvement in maintaining health and responding to environmental challenges.
The Body’s Natural Defender
Antimicrobial peptides (AMPs) are small, positively charged molecules that serve as a first line of defense against invading microorganisms. LL-37, the sole human cathelicidin, is derived from the precursor protein hCAP-18. It is produced in many areas of the human body, including the skin, lungs, gastrointestinal tract, and in various immune cells like neutrophils, monocytes, macrophages, and epithelial cells.
LL-37’s primary function involves direct antimicrobial activity against a broad spectrum of pathogens, including Gram-positive and Gram-negative bacteria, fungi, and some enveloped viruses. The peptide achieves this by interacting with and disrupting the outer membranes of these microbes. Its amphipathic structure, possessing both hydrophobic and hydrophilic regions, allows it to insert into the lipid bilayers of microbial membranes, forming pores that compromise cellular integrity and lead to cell death.
LL-37 also neutralizes bacterial endotoxins, such as lipopolysaccharide (LPS), which are components of Gram-negative bacterial cell walls that can trigger strong inflammatory responses. By binding to and inactivating these endotoxins, LL-37 helps to mitigate the harmful effects of bacterial infections.
Diverse Roles in Immunity
Beyond its direct antimicrobial actions, LL-37 modulates the immune response. It can influence inflammation, exhibiting both pro-inflammatory and anti-inflammatory effects depending on the cellular context. For instance, LL-37 can induce the release of pro-inflammatory mediators from macrophages and mast cells, such as CCL2 and CXCL8, which attract immune cells.
LL-37 also acts as a chemoattractant, drawing various immune cells, including neutrophils, monocytes, eosinophils, and mast cells, to sites of infection or injury. This activity is partly mediated through its interaction with receptors like formyl-peptide receptor-like 1 (FPRL1). The peptide also promotes tissue repair and wound healing by stimulating angiogenesis (the formation of new blood vessels), epithelialization (the formation of new epithelial tissue), and the migration and proliferation of skin cells like keratinocytes and fibroblasts.
LL-37 can disrupt bacterial biofilms, which are protective structures that shield bacteria from antibiotics and immune responses. It can penetrate these biofilms and exert its bactericidal effects on the embedded bacteria, making infections more susceptible to treatment. This capability is beneficial in chronic infections where biofilms contribute to persistent disease.
Implications for Health and Disease
Dysregulation of LL-37 levels, either too high or too low, can contribute to various health conditions. For example, overexpression of LL-37 is observed in several autoimmune diseases, including psoriasis and systemic lupus erythematosus (SLE). In psoriasis, LL-37 can form complexes with self-DNA, acting as an autoantigen that triggers an inflammatory cascade and contributes to the characteristic skin lesions. In lupus, LL-37 can enhance inflammation and potentially contribute to disease development.
Conversely, reduced levels of LL-37 have been linked to an increased risk of infections, such as those seen in patients with atopic dermatitis or chronic ulcers. In cystic fibrosis, elevated levels of LL-37 in lung mucus have been observed, and it can sometimes promote fungal growth. LL-37 has also been implicated in certain cancers, with its expression increased in some types like ovarian, lung, breast, and prostate cancers, where it can promote tumor growth. In contrast, lower levels have been noted in colon and gastric cancers.
Given its diverse functions, LL-37 and its derivatives hold therapeutic potential. It is being investigated as a novel antimicrobial agent, particularly against antibiotic-resistant pathogens, due to its broad-spectrum activity and ability to disrupt biofilms. Its immunomodulatory and wound-healing properties make it a candidate for treating chronic inflammatory conditions and accelerating the repair of persistent wounds, such as diabetic ulcers. While not yet FDA approved, ongoing research explores its applications in managing infections, chronic inflammatory conditions, and impaired wound healing.