Cathelicidin Peptide LL-37 and Inflammatory Conditions

The cathelicidin peptide LL-37, known for its antimicrobial properties, also plays a role in various inflammatory diseases such as psoriasis, lupus, rheumatoid arthritis, and atherosclerosis. LL-37 exhibits immune system modulating behaviors depending on the inflammatory environment and the specific cells involved. These behaviors include decreasing keratinocyte apoptosis, increasing IFN-alpha production, altering chemotaxis of neutrophils and eosinophils, down-regulating signaling through toll-like receptor 4 (TLR4), increasing IL-18 production, and decreasing levels of atherosclerotic plaques.

Interestingly, LL-37 does not consistently affect the immune system in the same manner. In cell culture experiments, it has been observed that the response of immune cells to LL-37 varies depending on their activation status. While T-cells increase their inflammatory actions in response to LL-37 when they are not activated, they decrease inflammatory action when already activated. These findings suggest that LL-37 has homeostatic effects that help balance the immune response, preventing excessive inflammation in the presence of infection. High levels of LL-37 in autoimmune diseases may actually be protective by preventing severe inflammation.

Antimicrobial Properties of LL-37

LL-37, as part of the innate immune system, is one of the first components to be activated during an infection. Research suggests that LL-37 accumulates rapidly in the presence of invading pathogens. The peptide works in conjunction with other proteins, such as human beta-defensin 2, to combat infections caused by bacteria. LL-37 primarily exerts its antimicrobial effects by binding to bacterial lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria. This binding interferes with LPS and is particularly effective against certain bacteria. There is ongoing interest in using LL-37 as an exogenous treatment for severe bacterial infections in humans.

Notably, while LL-37 primarily acts on gram-negative bacteria's cell membrane components, it also exhibits potent effects against gram-positive bacteria like Staphylococcus aureus. In vitro research indicates that LL-37 enhances the effects of lysozyme, an enzyme responsible for destroying gram-positive bacteria.

LL-37 and Lung Disease

Lipopolysaccharide (LPS) is not exclusive to bacterial cell walls; it can be present in other organisms as well. Inhaling LPS can trigger lung tissue to produce an immune response. However, this response is often insufficient to prevent toxic dust syndrome and the development of respiratory diseases such as asthma and COPD. Current research is investigating LL-37 as an inhaled treatment for toxic dust syndrome.

One interesting finding in LL-37 research related to lung disease is its role in promoting epithelial cell proliferation and wound closure. LL-37 appears to attract airway epithelial cells to the site of injury, facilitating wound healing and promoting the growth of blood vessels necessary for tissue recovery. LL-37 may act as a homeostatic regulator in the airways, similar to its role in immune function regulation.

Understanding LL-37 in Arthritis

Studies in rats have shown that LL-37 concentrations are elevated in joints affected by rheumatoid arthritis, suggesting an association with the pathological events of arthritis. However, it remains unclear whether LL-37 is causative or if its up-regulation is part of the body's attempt to control the disease. LL-37 deficiency does not affect outcomes in animal models of arthritis or lupus, indicating that LL-37 reactivity in arthritis is likely secondary to extensive peptide expression in inflamed tissues.

In mouse models, LL-37 and its derived peptides have demonstrated protective effects against collagen damage in inflammatory arthritis. Administration of these peptides to affected joints reduces disease severity and levels of antibodies against collagens. LL-37 and its derivatives have also been shown to regulate inflammation caused by interleukin-32, which is directly associated with inflammatory arthritis severity.

Toll-like receptor 3 up-regulation in synovial fibroblasts exacerbates arthritis. LL-37 binds to toll-like receptor 4 (TLR4) and can have both pro-inflammatory and anti-inflammatory effects. Its specific effects in the setting of TLR3 up-regulation are still under investigation. LL-37 has been found to selectively reduce pro-inflammatory macrophage responses, which supports the notion that it may reduce inflammation selectively.

LL-37 and Intestinal Health

LL-37 has several effects in the intestine, as demonstrated by cell culture research. It enhances the migration of cells crucial for maintaining the intestinal epithelial barrier. LL-37 also reduces apoptosis in the context of intestinal inflammation, slowing the progression of various inflammatory conditions. These findings suggest that LL-37 may be a useful adjuvant treatment in inflammatory bowel diseases, post-intestinal surgery, and acute intestinal infections. Additionally, LL-37 may serve as an adjuvant to antibiotic therapy, helping to mitigate the gastrointestinal side effects associated with oral antibiotic use.

In the intestines, LL-37 collaborates with human beta defensin 2 to promote wound healing and repair while reducing tumor necrosis factor (TNF)-related cell death. Such findings hold promise in reducing the reliance on TNF-alpha inhibitors for inflammatory bowel conditions, which have notable side effects including increased susceptibility to serious infections like tuberculosis.

LL-37 and Blood Vessel Growth

LL-37 triggers the synthesis of prostaglandin E2 (PGE2) in endothelial cells. PGE2 is associated with both inflammatory pain and angiogenesis (blood vessel growth), depending on its expression location. LL-37's ability to regulate angiogenesis is of particular interest due to its implications in cancer development, heart disease, stroke outcomes, wound healing, and more. Understanding LL-37's activity in the angiogenesis pathway can provide insights for potential interventions to promote or inhibit blood vessel growth in different contexts.