Cathelicidins are a large family of proteins with many different roles, one of which is the peptide known as LL-37. Macrophages and polymorphonuclear leukocytes (two kinds of white blood cells) create peptides with bactericidal activity. It has been discovered that they also have other significant impacts. Antimicrobial peptides (AMPs) are a common term for this category. Specifically, studies on LL-37 have been conducted within the contexts of autoimmune illness, cancer, and wound healing.[i] One study states, “Corneal and conjunctive epithelia express LL-37 as part of mucosal innate defenses to protect against bacterial and viral ocular infections.”
Inflammation and LL-37 Peptide
LL-37, while mainly recognized as an antimicrobial peptide, has also been researched within the context of in several inflammatory illnesses such as lupus, rheumatoid arthritis, psoriasis, and atherosclerosis. Researchers working with LL-37 have hypothesized that the peptide may modulate the immune system in various ways, depending on the types of cells involved and the local inflammatory milieu. It was proposed that LL-37 may:
- Potentially decrease keratinocyte apoptosis.
- Potentially enhance the production of interferon-alpha.
- Potentially reduce toll-like receptor 4 (TLR4) signaling.
- Potentially alter neutrophil and eosinophil chemotaxis.
- Potentially incite the release of interleukin-18.
- Potentially reduce atherosclerotic plaque.
Curiously, LL-37 (also known as CAP-18) seems to activate the immune system in a way that varies with the stimulus. Researchers working with cell cultures have suggested that inflammation plays a major role in influencing the immunological response to LL-37. Research suggests that LL-37 seems to have an opposing impact on T-cells, enhancing their inflammatory activity while not activated but dampening them once triggered. It seems that the peptide may mediate the homeostasis of the immune response, keeping it from becoming overactive when an illness strikes. In autoimmune illnesses, it may help reduce inflammation. Peptide concentrations are highly predictive of disease severity. Although LL-37 / CAP-18 was formerly considered to exacerbate autoimmune illnesses, new data suggests it may aid in mitigating the harm caused by these conditions. Researchers speculate that the peptide may be involved “in the modulation of immune and inflammatory ways and their impacts on autoimmune and inflammatory diseases.” Animal studies suggest that exposure to high concentrations of the peptide might thus limit the spread of inflammation.
LL-37 Peptide and Antimicrobial Potential
Investigations purport that when confronted with an infection, LL-37 seems to be one of the first proteins to become active. While the peptide is normally present in low concentrations in the skin, studies on skin infections have suggested that its levels may rapidly increase in the presence of invading pathogens. It has also been hypothesized it may cooperate with other proteins, such as beta-defensin 2, to combat infection. The outer membrane lipopolysaccharide (LPS) of gram-negative bacteria seems to be a binding site for LL-37. LPS ensures that these bacteria’s membranes stay intact. Toxic to certain bacteria, LL-37 may be able to bind to and interfere with LPS. LL-37 suggests promise as a potential agent in the context of staph infections and other life-threatening gram-positive bacterial infections. Lysozyme is effective against gram-positive bacteria like Staph aureus, and in vitro studies suggest that LL-37 / CAP-18 may enhance its actions.
LL-37 Peptide and Infections
LPS is present in various species and may be released into the air via fungal or mold contamination. When exposed to LPS, healthy lungs produce mucus as a protective mechanism. Responses typically fall short of what is needed to prevent toxic dust syndrome and other respiratory conditions, such as asthma and chronic obstructive pulmonary disease (COPD). Findings imply that toxic dust syndrome may be aided by LL-37 when breathed. Researchers speculate that in lung illnesses, LL-37 seems to encourage the growth of epithelial cells and the healing of lesions. The peptide may aid in vascularization, wound healing, and nutrient delivery to the newly created tissue by attracting airway epithelial cells to damaged areas, scientists hypothesize. Therefore, investigation results propose the peptide may serve as a mediator for immune activity and airway homeostasis.
LL-37 Peptide and Arthritis
Researchers found elevated amounts of LL-37 in the joints of arthritic rats. Whether or not this is what causes the illness or what can fix it is a mystery for the time being. Nonetheless, several results suggest the peptide may have value in inflammatory conditions. Research findings on animal models of arthritis and lupus suggested a lack of LL-37 did not appear to affect disease progression. The illness result may be the same in peptide-expressing animals as in peptide-deficient animals. These findings suggest that the observed physiologic responses of elevated cathelicidin levels in arthritis may be coincidental.
It has been proposed that LL-37 peptides may mitigate collagen damage in inflammatory arthritis. The severity of arthritis and the number of antibodies in the blood targeting type II collagen seemed reduced in rats when these peptides were given directly into the affected joints. It has been speculated that interleukin-32 (IL-32) may directly affect the severity of inflammatory arthritis. Studies suggested that LL-37 and related molecules may control how much an IL-32 response is mounted. Therefore, assuming that the peptide may have a protective effect in this illness model is plausible.
By upregulating the production of inflammatory cytokines, synovial fluid fibroblasts exacerbate the arthritic state. It is unclear if LL-37’s interaction with TLR4 may have a pro-inflammatory or anti-inflammatory effect. Whether or not LL-37/CAP-18 may mediate the same effect in the context of elevated TLR3 has to be determined. It has been proposed that the peptide may specifically inhibit pro-inflammatory macrophage responses, which provides data for the specificity of the peptide’s control of inflammation.
LL-37 Peptide and Intestinal Cancer
Multiple roles for LL-37 in the gut have been hypothesized in cell culture experiments. The peptide has been proposed to enhance cell migration, which is critical for keeping the intestinal epithelial barrier intact. When intestinal inflammation occurs, LL-37 has been speculated to assist in limiting apoptosis to lessen the inflammatory response and its associated pathophysiology. Research suggests that after intestinal surgery, during acute intestinal infections, the peptide may act as a helpful adjuvant to reduce or eliminate gastrointestinal (GI) side effects. Research suggests that when combined with beta-defensin 2, LL-37 for sale may expedite the healing of wounds. The peptides have been proposed to repair and maintain the intestinal epithelium and to reduce TNF-related cell death in in vitro studies.
References
[i] Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ, McDermott AM. Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res. 2005 May;30(5):385-94. doi: 10.1080/02713680590934111. PMID: 16020269; PMCID: PMC1497871.
[ii] Alalwani SM, Sierigk J, Herr C, Pinkenburg O, Gallo R, Vogelmeier C, Bals R. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. Eur J Immunol. 2010 Apr;40(4):1118-26. doi: 10.1002/eji.200939275. PMID: 20140902; PMCID: PMC2908514.
[iii] Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol. 2013 Nov 15;191(10):4895-901. doi: 10.4049/jimmunol.1302005. PMID: 24185823; PMCID: PMC3836506.
[iv] Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012 May;24(2):126-35. doi: 10.5021/ad.2012.24.2.126. Epub 2012 Apr 26. PMID: 22577261; PMCID: PMC3346901.
[v] Golec M. Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide. Ann Agric Environ Med. 2007;14(1):1-4. PMID: 17655171.
[vi] Moreno-Angarita A, Aragón CC, Tobón GJ. Cathelicidin LL-37: A new important molecule in the pathophysiology of systemic lupus erythematosus. J Transl Autoimmun. 2019 Dec 17;3:100029. doi: 10.1016/j.jtauto.2019.100029. PMID: 32743514; PMCID: PMC7388365.
