LL-37 peptide has been extensively studied for its potential in various research cases, and the one we will focus on here is the exploration of this peptide’s action in tissue research.
Cathelicidin (LL-37) is a 37-amino-acid cationic peptide abundant in neutrophils [i]. The protease-catalyzed extracellular degradation of hCAP18 proteins seems to be the source of LL-37. Studies suggest the peptide’s potential to form agglomerates and lipid bilayers, LL-37, which is being studied for its possible antibacterial characteristics and may not be readily degraded, and may be shielded from enzymatic activity [i].
LL-37 Peptide Overview
Antimicrobial peptides are designed to kill microorganisms, including bacteria, fungi, and even certain viruses. Researchers believe that infections might not acquire resistance once the peptide is introduced possibly due to the peptide's proposed non-specific interaction with targets [ii].
Scientists speculate LL-37, a -helical peptide, may be actionable for continued protection against all microorganisms [iii]. Based on the idea that the peptide may interact directly with the bacterial membrane, a peptide model was developed as part of the investigation [iv]. This research suggests the peptide may assemble on the bacterial membrane after it has diffused laterally and interacted with the membrane's lipids through its electrostatic properties. Interference with the membrane and subsequent cell death in bacteria would result from such a meeting.
Other studies have hypothesized how the peptide may interact with microbial membranes, with some suggesting that pores may form on the membrane [iii, v] and others suggesting that the peptide and lipid complexes may cause severe membrane disruption [vi]. These investigations suggest that LL-37 peptides may interact with the microbial membrane, which might dissolve the membrane.
LL-37 Peptide Research and Clinical Investigations
Peptide LL-37 and Inflammation
This research's primary motivation was to determine how inflammatory the LL-37 peptide may be. Tissue culture was employed, with half of the cultures being left alone and the other half having U1 RNA added to them. U1 RNA is a non-coding RNA widely distributed in the body and thought to be produced in response to tissue damage. Both cultures were then given LL-37 peptide. Researchers speculated that the culture presented with U1 RNA and LL-37 peptide appeared to have a substantial reaction towards epidermal (skin) inflammation and a defensive response based on genetic analyses.
LL-37 Peptide and Joints
This research aimed to assess the potential of LL-37 in arthritic joints [i, vii] This research used eight rats and two groups: a control group and an artificially produced rheumatoid arthritis group. Scientists reported an apparent upregulation of rCRAMP, the rat homolog of LL-37 peptide, in inflammatory cells. Scientists hypothesized that LL-37 peptide, by inducing apoptosis of osteoblasts, might reduce bone formation in the joints.
Researchers have speculated that cells exposed to arteriosclerosis may trigger LL-37 activation, increasing interferon expression. This study's authors hypothesized that LL-37 may be useful as an immunomodulatory agent.
LL-37 Peptide and Tissue
To investigate the potential of LL-37 on angiogenesis and wound healing, researchers in this study [viii] presented the peptide to mice after they had been exposed to an anti-inflammatory compound. The researchers suggested that the peptide mice seemed to have enhanced vascularization and skin cell production. This analysis suggests that LL-37 may stimulate the growth of endothelial skin cells and the development of tubule-like structures, both of which are necessary for angiogenesis.
LL-37 Peptide And Cells
The potential role of LL-37 peptide in the progression of cancer cells is the subject of continuing research [ix]. Some research [ix] suggests LL-37 may potentially reduce the growth of gastric cancer cells by stimulating the bone morphogenetic protein signaling pathway. The primary goal of this study [ix] was to investigate LL-37 for its potential immunological action, or LL-37 peptide as an adjuvant in the destruction of host-based cancer cells. Since CpG oligodeoxynucleotides appear to boost tumor-suppressing activities, they are widely considered immunotherapeutic agents. It has been hypothesized that presenting lymphocytes with the peptide LL-37 may increase their sensitivity to CpG oligodeoxynucleotides.
LL-37 Peptide and Lysosomes
LL-37 has been studied for its potential to mitigate the impact of gastrointestinal (GI) disfunction. Research suggests subjects with stomach ulcers appear to have elevated LL-37 expression. Scientists speculate that due to its alleged antibacterial properties, LL-37 may be able to mitigate the impact of infections in the stomach and gastrointestinal tract. [x]
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References
[i] Kahlenberg, J Michelle, and Mariana J Kaplan. “Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease.” Journal of immunology (Baltimore, Md. : 1950) vol. 191,10 (2013): 4895-901. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836506/
[ii] Seil, M., Nagant, C., Dehaye, J. P., Vandenbranden, M., & Lensink, M. F. (2010). Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties. Pharmaceuticals, 3(11), 3435–3460. h https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034075/
[iii] Zeth, Kornelius, and Enea Sancho-Vaello. “The Human Antimicrobial Peptides Dermcidin and LL-37 Show Novel Distinct Pathways in Membrane Interactions.” Frontiers in chemistry vol. 5 86. 7 Nov. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681987/
[iv] Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005 Mar;3(3):238-50. https://pubmed.ncbi.nlm.nih.gov/15703760/
[v] Ludtke SJ, He K, Heller WT, Harroun TA, Yang L, Huang HW. Membrane pores induced by magainin. Biochemistry. 1996 Oct 29;35(43):13723-8. https://pubmed.ncbi.nlm.nih.gov/8901513/
[vi] Bechinger B, Lohner K. Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim Biophys Acta. 2006 Sep;1758(9):1529-39. https://pubmed.ncbi.nlm.nih.gov/16928357/
[vii] Hoffmann MH, Bruns H, Bäckdahl L, Neregård P, Niederreiter B, Herrmann M, Catrina AI, Agerberth B, Holmdahl R. The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis. 2013 Jul;72(7): https://pubmed.ncbi.nlm.nih.gov/23172753/
[viii] Ramos R, Silva JP, Rodrigues AC, Costa R, Guardão L, Schmitt F, Soares R, Vilanova M, Domingues L, Gama M. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011 Jul;32(7):1469-76. doi: 10.1016/j.peptides.2011.06.005. Epub 2011 Jun 13. https://pubmed.ncbi.nlm.nih.gov/21693141/
[ix] Wu, W. K., Wang, G., Coffelt, S. B., Betancourt, A. M., Lee, C. W., Fan, D., Wu, K., Yu, J., Sung, J. J., & Cho, C. H. (2010). Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. International journal of cancer, 127(8), 1741–1747. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930073/
[x] Kusaka; et al. Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease. Clin Exp Immunol. 2018 Jan;19(11). Epub 2017 Sep 28. https://pubmed.ncbi.nlm.nih.gov/28872665/
