LL-37 is the only known human member of the cathelicidin family of antimicrobial peptides, a multifunctional 37-amino acid peptide derived from the hCAP18 precursor protein. Research reveals its complex biological activities spanning antimicrobial defense, tissue repair, immune modulation, and cellular signaling pathways.
Direct Antimicrobial Mechanisms
LL-37 exhibits dual membrane interaction pathways dependent on lipid composition. The peptide forms pores in bilayers of unsaturated phospholipids while creating nanofibers in saturated phospholipids, switching mechanisms based on alkyl chain structure rather than lipid head groups[1].
Real-time microscopy studies reveal that LL-37 saturates the outer membrane within 1 minute and translocates across the periplasmic space[2]. The peptide forms toroidal pores through oligomers that generate fibril-like supramolecular structures on target membranes[3].
Crystal structure analysis shows that LL-37’s active core self-assembles into densely packed hexameric fibrillar architectures. These fibrils feature alternating hydrophobic and positively charged zigzagged belts that interact with negatively charged bacterial membranes[4].
Wound Healing and Tissue Repair
LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through ERK and Akt signaling pathways[5]. The peptide enhances angiogenesis by providing continuous angiogenesis-promoting signals and can restore wound microenvironments by scavenging reactive oxygen species[6].
Research shows LL-37 accelerates re-epithelialization of both nondiabetic and diabetic wounds[7]. When delivered via electroporation, the peptide causes significant VEGF expression and promotes high-quality tissue repair[8].
The peptide promotes wound healing via EGFR transactivation, particularly in high-glucose conditions[9]. LL-37 also stimulates heparin-binding EGF-like growth factor shedding and enhances EGFR signaling pathways[9].
Immunomodulatory Functions
LL-37 modulates dendritic cell differentiation and promotes Th1 responses by enhancing endocytic capacity and upregulating costimulatory molecule expression[10]. The peptide regulates macrophage cell surface GAPDH and alters internalization mechanisms[11].
Studies show LL-37 enhances neutrophil extracellular trap release with potent bactericidal activity[12]. The peptide stimulates neutrophils to release antimicrobial microvesicles that improve pathological conditions in research models[13].
LL-37 suppresses pro-inflammatory macrophage pyroptosis by neutralizing LPS action and inhibiting P2X7 receptor responses[14]. The peptide shows dual pro- and anti-inflammatory effects depending on tissue context and concentrations[15].
Cancer and Cell Death Pathways
In cancer research, LL-37 shows concentration-dependent anti-cancer effects against multiple cell lines[16]. In pancreatic cancer models, the peptide inhibits growth through DNA damage and cell cycle arrest via reactive oxygen species induction[17].
LL-37 induces caspase-independent apoptosis in colon cancer cells through nuclear translocation of apoptosis-inducing factor and endonuclease G[18]. Research shows the peptide was strongly expressed in normal colon mucosa but downregulated in cancer tissues[19].
However, LL-37 can also demonstrate pro-tumorigenic functions in certain contexts. The peptide activates TRPV2 calcium-permeable channels and promotes epithelial-mesenchymal transition in hepatocellular carcinoma models[20][21].
Autoimmune and Inflammatory Research
LL-37 serves as a key autoantigen in psoriasis through post-translational modifications[22]. Citrullination and carbamylation of LL-37 create modified epitopes that dictate autoreactive T-helper cell polarization[23].
The peptide forms complexes with self-DNA/RNA that act as type I interferon triggers in psoriatic inflammation[24]. Anti-LL37 antibodies are present in psoriatic arthritis patients, with antibodies to carbamylated-LL37 correlating with disease activity scores[25].
Research shows LL-37 contributes to Alzheimer’s disease progression through interactions with amyloid pathways[26]. The peptide acts as a nanomolar inhibitor of amyloid self-assembly and binds amyloid-β with specificity[27][28].
Viral Interactions and Antiviral Activity
LL-37 shows direct antiviral activity against multiple virus families[29]. The peptide exhibits antiviral activity against respiratory syncytial virus by inducing direct damage to viral envelopes and disrupting viral particles[30].
Against influenza A viruses, LL-37 disrupts viral membranes without inducing viral aggregation[31]. Studies show the peptide requires direct interaction with virus particles for antiviral efficacy[32].
Viruses can evade LL-37 activity through citrullination mechanisms. Rhinovirus infection upregulates PAD2 protein expression and increases protein citrullination levels, including histone H3 modifications[32].
References
[1] M. Shahmiri, M. Enciso, C. G. Adda, B. J. Smith, M. A. Perugini, and A. Mechler, “Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation,” Springer Science and Business Media LLC, Nov. 2016. doi: 10.1038/srep38184.
[2] K. A. Sochacki, K. J. Barns, R. Bucki, and J. C. Weisshaar, “Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL-37,” Proceedings of the National Academy of Sciences, Apr. 2011. doi: 10.1073/pnas.1101130108.
[3] K. Pastuszak, M. Jurak, B. Kowalczyk, J. Tarasiuk, A. E. Wiącek, and M. Palusińska-Szysz, “Susceptibility of Legionella gormanii Membrane-Derived Phospholipids to the Peptide Action of Antimicrobial LL-37—Langmuir Monolayer Studies,” MDPI AG, Mar. 2024. doi: 10.3390/molecules29071522.
[4] Y. Engelberg and M. Landau, “The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure,” Springer Science and Business Media LLC, Aug. 2020. doi: 10.1038/s41467-020-17736-x.
[5] T. Yanagisawa, M. Ishii, M. Takahashi, K. Fujishima, and M. Nishimura, “Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways,” Springer Science and Business Media LLC, Sep. 2020. doi: 10.1007/s11033-020-05741-8.
[6] R. Shi et al., “Self‐assembly of PEG–PPS polymers and LL‐37 peptide nanomicelles improves the oxidative microenvironment and promotes angiogenesis to facilitate chronic wound healing,” Wiley, Nov. 2023. doi: 10.1002/btm2.10619.
[7] A. J. Duplantier and M. L. van Hoek, “The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds,” Frontiers Media SA, 2013. doi: 10.3389/fimmu.2013.00143.
[8] L. Steinstraesser et al., “Skin Electroporation of a Plasmid Encoding hCAP-18/LL-37 Host Defense Peptide Promotes Wound Healing,” Elsevier BV, Apr. 2014. doi: 10.1038/mt.2013.258.
[9] J. Yin and F.-S. X. Yu, “LL-37 via EGFR Transactivation to Promote High Glucose–Attenuated Epithelial Wound Healing in Organ-Cultured Corneas,” Association for Research in Vision and Ophthalmology (ARVO), Apr. 2010. doi: 10.1167/iovs.09-3904.
[10] F. Torres-Juarez et al., “LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages,” American Society for Microbiology, Dec. 2015. doi: 10.1128/iai.00936-15.
[11] A. Dhiman et al., “Regulation of Macrophage Cell Surface GAPDH Alters LL-37 Internalization and Downstream Effects in the Cell,” S. Karger AG, 2023. doi: 10.1159/000530083.
[12] I. Nagaoka, H. Tamura, and J. Reich, “Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model,” MDPI AG, Aug. 2020. doi: 10.3390/ijms21175973.
[13] Z. Hu et al., “Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice,” Oxford University Press (OUP), Jan. 2016. doi: 10.1093/intimm/dxv113.
[14] M. T. Martín Monreal et al., “Characterization of circulating extracellular traps and immune responses to citrullinated LL37 in psoriasis,” Frontiers Media SA, Dec. 2023. doi: 10.3389/fimmu.2023.1247592.
[15] D. Svensson and B.-O. Nilsson, “Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update,” Springer Science and Business Media LLC, Feb. 2025. doi: 10.1007/s00011-025-02005-8.
[16] K. Kuroda et al., “miR-663a regulates growth of colon cancer cells, after administration of antimicrobial peptides, by targeting CXCR4-p21 pathway,” Springer Science and Business Media LLC, Jan. 2017. doi: 10.1186/s12885-016-3003-9.
[17] Z. Zhang et al., “The human cathelicidin peptide LL-37 inhibits pancreatic cancer growth by suppressing autophagy and reprogramming of the tumor immune microenvironment,” Frontiers Media SA, Jul. 2022. doi: 10.3389/fphar.2022.906625.
[18] S. X. Ren et al., “Host Immune Defense Peptide LL-37 Activates Caspase-Independent Apoptosis and Suppresses Colon Cancer,” American Association for Cancer Research (AACR), Dec. 2012. doi: 10.1158/0008-5472.can-12-2359.
[19] K. Niemirowicz et al., “Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells,” Informa UK Limited, Jun. 2015. doi: 10.2147/ijn.s76104.
[20] A. Gambade et al., “Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells,” Impact Journals, LLC, Mar. 2016. doi: 10.18632/oncotarget.8122.
[21] K. Kuroda, K. Okumura, H. Isogai, and E. Isogai, “The Human Cathelicidin Antimicrobial Peptide LL-37 and Mimics are Potential Anticancer Drugs,” Frontiers Media SA, Jun. 2015. doi: 10.3389/fonc.2015.00144.
[22] R. Lande et al., “The nature of the post-translational modifications of the autoantigen LL37 influences the autoreactive T-helper cell phenotype in psoriasis,” Frontiers Media SA, Apr. 2025. doi: 10.3389/fimmu.2025.1546422.
[23] L. Frasca et al., “Anti-LL37 Antibodies Are Present in Psoriatic Arthritis (PsA) Patients: New Biomarkers in PsA,” Frontiers Media SA, Sep. 2018. doi: 10.3389/fimmu.2018.01936.
[24] J. Lao, Z. Xie, Q. Qin, R. Qin, S. Li, and Y. Yuan, “Serum LL‐37 and inflammatory cytokines levels in psoriasis,” Wiley, Mar. 2023. doi: 10.1002/iid3.802.
[25] J. Fuentes-Duculan et al., “004 Autoantigens ADAMTSL5 and LL-37 are significantly upregulated in active psoriasis and associated with dendritic cells and macrophages,” Elsevier BV, May 2017. doi: 10.1016/j.jid.2017.02.017.
[26] X. Chen et al., “Human antimicrobial peptide LL-37 contributes to Alzheimer’s disease progression,” Springer Science and Business Media LLC, Sep. 2022. doi: 10.1038/s41380-022-01790-6.
[27] E. De Lorenzi et al., “Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-β and Inhibitor of Fibril Assembly,” SAGE Publications, Aug. 2017. doi: 10.3233/jad-170223.
[28] V. Armiento, K. Hille, D. Naltsas, J. S. Lin, A. E. Barron, and A. Kapurniotu, “The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP),” Wiley, Apr. 2020. doi: 10.1002/anie.202000148.
[29] S. M. Currie et al., “Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans,” Oxford University Press (OUP), Mar. 2016. doi: 10.4049/jimmunol.1502478.
[30] S. M. Currie et al., “The Human Cathelicidin LL-37 Has Antiviral Activity against Respiratory Syncytial Virus,” Public Library of Science (PLoS), Aug. 2013. doi: 10.1371/journal.pone.0073659.
[31] S. Tripathi, T. Tecle, A. Verma, E. Crouch, M. White, and K. L. Hartshorn, “The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins,” Microbiology Society, Jan. 2013. doi: 10.1099/vir.0.045013-0.
[32] V. Casanova et al., “Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection,” Frontiers Media SA, Feb. 2020. doi: 10.3389/fimmu.2020.00085.
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