LL-37 is the only cathelicidin (a type of infection-fighting peptide) that humans naturally produce. Skin cells, gut cells, lung cells, and immune cells like neutrophils and monocytes all release it when they sense a threat, and it does double duty: punching holes in bacteria and fungi to kill them, and acting as a signal that calls in the rest of the immune system. Scientists have studied it for two decades as a template for new anti-infective drugs, wound treatments, and even cancer therapies. But almost everything known about it comes from lab dishes, animal models, and studies that simply measure the LL-37 people already have in their blood or tissue — not from giving people LL-37 as a treatment.
How strong is the evidence?
Of the 40 papers reviewed, the large majority are lab experiments (cell cultures), animal studies (mostly mice), and review articles summarizing that work. A smaller group are human studies — but these measure the LL-37 people's own bodies are already making in blood, saliva, or tissue samples (for example, in gum disease or lupus patients) rather than testing LL-37 given as a treatment. No clinical trial has ever dosed people with LL-37 to test whether it works or is safe as a therapy. That makes this a preclinical (animal/lab-stage) compound: the biology is well mapped, but the leap to a usable human treatment hasn't happened yet.
Uses
What people use it for
Fighting bacterial, fungal, and viral infections
Animal / labLL-37 kills a wide range of bacteria and fungi and can break down the slimy 'biofilms' bacteria hide in, which is a big reason drug-resistant infections are so hard to treat. It also blocks a step SARS-CoV-2 needs to infect cells. All of this is shown in lab dishes and animal models, not in treated patients.
Helping wounds and damaged skin heal
Animal / labLL-37 helps skin cells move and multiply to close a wound, and it encourages new blood vessels to grow into healing tissue. Diabetic mice treated with LL-37 healed wounds faster in lab studies.
Cancer research (a genuinely mixed picture)
Animal / labLL-37 can kill some cancer cells directly, but in other cancers (ovarian, lung, breast) it appears to help tumors grow instead. Researchers are still working out which effect wins in which cancer type.
Understanding autoimmune and inflammatory disease
Some human dataDoctors have measured LL-37 levels in real patients with gum disease, lupus, psoriasis, and Kawasaki disease, and found it's often elevated and tied to how active the disease is. This makes it a useful biomarker and research clue, not a treatment.
Template for safer, lab-designed antimicrobial peptides
Animal / labBecause natural LL-37 is unstable and can be toxic to the body's own cells at high doses, chemists are re-engineering it into modified versions (like 17BIPHE2) that keep the germ-killing power while being more stable and less likely to harm human cells.
Potential benefits
What it may help with
Kills bacteria, fungi, and blocks some viruses
Animal / labLL-37 punches holes in the outer coating of many bacteria and fungi, and breaks up the protective biofilms some bacteria build to resist antibiotics. It also blocks a key step the SARS-CoV-2 virus needs to get into cells (though this doesn't work against newer Omicron variants, which mutated to dodge it).
Speeds up wound healing in lab and animal studies
Animal / labIt helps skin cells migrate to close wounds faster and encourages new blood vessel growth. In diabetic mice, a group that famously heals wounds slowly, LL-37 sped up wound closure.
May help clear excess cholesterol from the blood and liver
Animal / labIn mice prone to high cholesterol, LL-37 attached to LDL ('bad') cholesterol particles and helped the liver clear them out, reducing fat buildup in the liver. This is a very new, single-study finding in mice, not humans.
Studies:40971038Helps immune cells turn into bone-repair cells
TheoryLL-37 gets absorbed by monocytes (a type of immune cell) and appears to help guide them into becoming 'monoosteophils,' a specialized cell type involved in repairing bone. This is early lab-level cell biology, not a demonstrated bone-healing therapy.
Studies:31886324Can kill certain cancer cells
Animal / labIn colon, stomach, and some blood and oral cancers, LL-37 has shown a direct cancer-killing effect in lab studies. (Note: in other cancer types it can do the opposite — see side effects.)
What to watch for
Side effects & risks
- Moderate
- Moderate
May fuel autoimmune disease activity
LL-37 can bind to a person's own DNA and set off an immune reaction that looks a lot like what happens in lupus, where it's considered a genuine driver of disease activity, not just a bystander.
- Moderate
Can damage the gut lining
In lab experiments on gut-lining cells, LL-37 broke down the 'seals' between cells that normally keep the intestine barrier tight, making it leakier. This effect made things worse, not better, when combined with a gut infection in cell studies.
- Moderate
Can be toxic to some of the body's own cells at higher levels
At concentrations the body can realistically produce (boosted by vitamin D), LL-37 killed bone-building cells (osteoblasts) in lab dishes and triggered cell death in blood-vessel lining cells with certain underlying vulnerabilities. It also pushes infected airway cells toward cell death.
- Moderate
Linked to harmful blood-vessel inflammation
In children with Kawasaki disease (a condition that inflames blood vessels), blood LL-37 levels were elevated, and lab experiments showed it directly triggers an inflammatory chain reaction in the cells lining coronary arteries.
Dosing
Dosing — what studies used
There is no established human dose for LL-37, and no clinical trial has ever given it to people as a treatment. Every 'dose' in the literature is either a lab concentration used on cells in a dish, or an unspecified amount given to mice in an experiment. Anyone encountering LL-37 sold as a research or self-injection product should understand that there is no science establishing what a safe or effective human dose would even look like — this is genuinely uncharted territory, not just an under-researched one.
Because LL-37 has shown real toxicity to the body's own cells (bone-building cells, blood vessel lining) at concentrations the body itself can reach, and because it can worsen autoimmune and gut conditions, self-administering it without medical supervision and without any established dosing data carries real, unquantified risk.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Think of LL-37 as a small, positively charged molecular hook. Bacteria and fungi have negatively charged outer coatings, so LL-37 is drawn straight to them, punches into their outer membrane, and breaks it open, killing the microbe. At the same time, LL-37 acts like a flare that immune cells recognize, calling in reinforcements and telling nearby cells to ramp up inflammation and healing. It also gets absorbed into immune cells like monocytes, where it helps direct what those cells turn into next. That same 'punch a hole and set off alarms' strategy is why LL-37 is a double-edged sword: in the right place and amount, it clears infection and helps tissue heal; in the wrong place, or at too high a concentration, it can damage the body's own cells and over-trigger inflammation.
Who should avoid it
- Anyone with an autoimmune condition such as lupus, psoriasis, or rosacea — the evidence links LL-37 to flares of these diseases.
- Anyone with inflammatory bowel disease or gut permeability problems, since lab studies show it can damage the gut lining.
- Anyone with a history of blood-vessel inflammation (such as Kawasaki disease) or atherosclerosis risk, given its link to vessel inflammation and cell damage in these settings.
- In truth, no one should be self-administering LL-37 outside a research setting — there is no established human dose, safety record, or approved use.
Interactions to know
- No formal drug-interaction studies exist in people, because LL-37 has never been used as a human drug.
- Vitamin D directly boosts the body's own production of LL-37, so vitamin D supplements or sun exposure raise your natural levels — this is a real biological link, not a tested drug interaction.
- In early lab and animal research, LL-37 is being combined with antibiotics and bacteria-killing viruses (phages) to fight drug-resistant infections more effectively together than either alone.
The papers that matter most
Key studies
The best single overview of what LL-37 does: kills microbes, fights biofilms, helps wounds heal, and has a complicated, two-sided relationship with cancer.
Unique features of human cathelicidin LL-37
Shows vitamin D strongly raises the body's own LL-37 production — and that at the levels this reaches, LL-37 can kill bone-building cells in the lab.
Vitamin D triggers hCAP18/LL-37 production: Implications for LL-37-induced human osteoblast cytotoxicity
LL-37 blocks a key step SARS-CoV-2 needs to enter cells, but the virus's Omicron mutations dodge this defense.
LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants
In diabetic mice, which normally heal wounds slowly, LL-37 sped up wound closure by activating a cellular cleanup process.
Cathelicidin LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy
LL-37 broke down the tight seals between gut-lining cells, making the intestinal barrier leakier — a genuine risk signal, not just a benefit story.
Human cathelicidin LL-37 rapidly disrupted colonic epithelial integrity
Lays out the case that LL-37 is an active driver of lupus flares, not just a marker of the disease.
Cathelicidin LL-37: A new important molecule in the pathophysiology of systemic lupus erythematosus
Bottom line
LL-37 is a fascinating molecule that your own body already makes to fight infection and help wounds heal, and it's a serious research target for future antibiotics and wound treatments. But it has never been tested as a therapy in people — every human data point comes from measuring the peptide the body already produces, not from giving someone a dose of it. Given real evidence that it can also damage the body's own cells and worsen autoimmune and gut problems, there's currently no responsible way to use it outside a research lab.
Research papers
Studies we have on file for LL-37. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Vitamin D triggers hCAP18/LL-37 production: Implications for LL-37-induced human osteoblast cytotoxicity.
The human cathelicidin LL-37 shows activity against microorganisms, but it is also cytotoxic to host cells. The CAMP gene codes for the LL-37 precursor hCAP18 which is processed extracellularly to active LL-37. It has previously been shown that vitamin D stimulates CAMP gene activity, but less information is available demonstrating that vitamin D also can increase hCAP18/LL-37 protein production. Here, we show with RT-qPCR that a physiological concentration of vitamin D (50 nM) enhances CAMP mRNA levels by about 170 times in human THP-1 monocyte cells. Stimulation with 50 nM vitamin D increases hCAP18/LL-37 protein contents 3-4 times in THP-1 cell lysates demonstrated by both dot blot analysis and ELISA applying two different hCAP18/LL-37 antibodies. Treatment with the proteasome inhibitor MG132 enhances hCAP18/LL-37 levels, suggesting that turnover of hCAP18/LL-37 protein is regulated by the proteasome. The hCAP18/LL-37 concentration in vitamin D-stimulated THP-1 cells corresponds to 1.04 μM LL-37. Interestingly, synthetic LL-37, at this concentration, reduces viability of human osteoblast-like MG63 cells, whereas the THP-1 cells are less sensitive as demonstrated by the MTT assay. In summary, we show that vitamin D enhances hCAP18/LL-37 production, and that this effect can be of physiological/pathophysiological relevance for LL-37-induced human osteoblast toxicity.
Cathelicidin LL-37 in Health and Diseases of the Oral Cavity.
The mechanisms for maintaining oral cavity homeostasis are subject to the constant influence of many environmental factors, including various chemicals and microorganisms. Most of them act directly on the oral mucosa, which is the mechanical and immune barrier of the oral cavity, and such interaction might lead to the development of various oral pathologies and systemic diseases. Two important players in maintaining oral health or developing oral pathology are the oral microbiota and various immune molecules that are involved in controlling its quantitative and qualitative composition. The LL-37 peptide is an important molecule that upon release from human cathelicidin (hCAP-18) can directly perform antimicrobial action after insertion into surface structures of microorganisms and immunomodulatory function as an agonist of different cell membrane receptors. Oral LL-37 expression is an important factor in oral homeostasis that maintains the physiological microbiota but is also involved in the development of oral dysbiosis, infectious diseases (including viral, bacterial, and fungal infections), autoimmune diseases, and oral carcinomas. This peptide has also been proposed as a marker of inflammation severity and treatment outcome.
Psoriasis and Antimicrobial Peptides.
Psoriasis is a systemic inflammatory disease caused by crosstalk between various cells such as T cells, neutrophils, dendritic cells, and keratinocytes. Antimicrobial peptides (AMPs) such as β-defensin, S100, and cathelicidin are secreted from these cells and activate the innate immune system through various mechanisms to induce inflammation, thus participating in the pathogenesis of psoriasis. In particular, these antimicrobial peptides enhance the binding of damage-associated molecular patterns such as self-DNA and self-RNA to their receptors and promote the secretion of interferon from activated plasmacytoid dendritic cells and keratinocytes to promote inflammation in psoriasis. Neutrophil extracellular traps (NETs), complexes of self-DNA and proteins including LL-37 released from neutrophils in psoriatic skin, induce Th17. Activated myeloid dendritic cells secrete a mass of inflammatory cytokines such as IL-12 and IL-23 in psoriasis, which is indispensable for the proliferation and survival of T cells that produce IL-17. AMPs enhance the production of some of Th17 and Th1 cytokines and modulate receptors and cellular signaling in psoriasis. Inflammation induced by DAMPs, including self-DNA and RNA released due to microinjuries or scratches, and the enhanced recognition of DAMPs by AMPs, may be involved in the mechanism underlying the Köbner phenomenon in psoriasis.
Antibiofilm properties of cathelicidin LL-37: an in-depth review.
Notwithstanding ceaseless endeavors toward developing effective antibiofilm chemotherapeutics, biofilm-associated infections continue to be one of the most perplexing challenges confronting medicine today. Endogenous host defense peptides, such as the human cathelicidin LL-37, are being propounded as promising options for treating such infectious diseases. Over the past decennium, LL-37 has duly received tremendous research attention by virtue of its broad-spectrum antimicrobial activity and immunomodulatory properties. No attempt has hitherto been made, as far as we are aware, to comprehensively review the antibiofilm effects of LL-37. Accordingly, the intent in this paper is to provide a fairly all-embracing review of the literature available on the subject. Accumulating evidence suggests that LL-37 is able to prevent biofilm establishment by different bacterial pathogens such as Acinetobacter baumannii, Aggregatibacter actinomycetemcomitans, Bacteroides fragilis, Burkholderia thailandensis, Cutibacterium acnes, Escherichia coli, Francisella tularensis, Helicobacter pylori, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes. Inhibition of bacterial adhesion, downregulation of biofilm-associated genes, suppression of quorum-sensing pathways, degradation of biofilm matrix, and eradication of biofilm-residing cells are the major mechanisms responsible for antibiofilm properties of LL-37. In terms of its efficacy and safety in vivo, there are still many questions to be answered. Undoubtedly, LL-37 can open up new windows of opportunity to prevent and treat obstinate biofilm-mediated infections.
Unique features of human cathelicidin LL-37.
Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds.
Recombinant expression of human cathelicidin (hCAP18/LL-37) in Pichia pastoris.
The constitutive expression of human cathelicidin LL-37 antimicrobial peptide was achieved using the methylotrophic yeast, Pichia pastoris. An LL-37 cDNA clone was amplified by PCR using human fetal cDNA library as template. The 111 bp fragment encoding mature LL-37 gene was subcloned into pGAPZ-E, an episomal form of the pGAPZB vector incorporating PARS1. It was then transformed into the P. pastoris X-33 strain for intracellular expression. A small peptide with a molecular mass of about 5 kDa was detected by 17% peptide-PAGE analysis. The recombinant LL-37 peptide was purified from the gel and its amino acid sequence was determined by LC-ESI-MS/MS analysis. The initiating amino acid, methionine, was still attached to the N-terminal region of recombinant LL-37. LL-37 crude extract from P. pastoris showed an antimicrobial activity against Micrococcus luteus as the test strain. The successful expression of human LL-37 indicates that the system may be applicable to the expression of other human defensins without resorting to fusion protein constructions.
Cathelicidin LL-37: a multitask antimicrobial peptide.
The antimicrobial peptide LL-37 is the only known member of the cathelicidin family of peptides expressed in humans. LL-37 is a multifunctional host defense molecule essential for normal immune responses to infection and tissue injury. LL-37 peptide is a potent killer of different microorganisms with the ability to prevent immunostimulatory effects of bacterial wall molecules such as lipopolysaccharide and can therefore protect against lethal endotoxemia. Additional reported activities of LL-37 include chemoattractant function, inhibition of neutrophil apoptosis, and stimulation of angiogenesis, tissue regeneration, and cytokine release (e.g. IL-8). Cellular production of LL-37 is affected by multiple factors, including bacterial products, host cytokines, availability of oxygen, and sun exposure through the activation of CAP-18 gene expression by vitamin D(3). At infection sites, the function of LL-37 can be inhibited by charge-driven interactions with DNA and F-actin released from dead neutrophils and other cells lysed as the result of inflammation. A better understanding of LL-37's biological properties is necessary for its possible therapeutic application for immunomodulatory purposes as well as in treating bacterial infection.
Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide.
Human organism, constantly exposed to a large variety of pathogenic microorganisms and their products, such as lipopolysaccharide (LPS), developed innate immunity as a first line of defence. One of the compartments of our organism well equipped with these defence mechanisms is the respiratory system. The cells lining the airways respond to the presence of virulent microorganisms by producing natural antimicrobial peptides, including the only member of the cathelicidins family found to date in humans, peptide LL-37. LL-37 is a small peptide of 37 amino acid residues. The peptide, in addition to its bactericidal effect, plays numerous roles in inflammatory and tissue remodelling processes. It stimulates angiogenesis, induces proliferation of lung epithelial cells, accelerates wound closure of the airway epithelium, and provokes cytokine release (e.g. IL-8) and cell migration. LL-37 is also able to neutralize LPS, a heteropolymer associated with organic dust, produced by Gram-negative bacteria. LPS (commonly referred to as endotoxin) plays an important role in pathogenesis of many respiratory diseases caused by organic dust, including organic dust toxic syndrome and chronic illnesses such as chronic obstructive pulmonary disease (COPD), asthma or allergic alveolitis (hypersensitivity pneumonitis). LPS is a strong pro-inflammatory stimulus, inducing in respiratory airways expression of antimicrobial peptides, including LL-37, which is in turn a potent LPS-neutralizing factor. The article discusses the complex interplay between endotoxin and the LPS-neutralizing, pleiotropic peptide LL-37 in pathogenic mechanisms of lung diseases, with regard to closer perspectives of using LL-37 and its derivatives as therapeutic agents.
The Role of Cathelicidin LL-37 in Cancer Development.
LL-37 is a C-terminal peptide proteolytically released from 18 kDa human cathelicidin protein (hCAP18). Chronic infections, inflammation, tissue injury and tissue regeneration are all linked with neoplastic growth, and involve LL-37 antibacterial and immunomodulatory functions. Such a link points to the possible involvement of LL-37 peptide in carcinogenesis. An increasing amount of evidence suggests that LL-37 can have two different and contradictory effects--promotion or inhibition of tumor growth. The mechanisms are tissue-specific, complex, and depend mostly on the ability of LL-37 to act as a ligand for different membrane receptors whose expression varies on different cancer cells. Overexpression of LL-37 was found to promote development and progression of ovarian, lung and breast cancers, and to suppress tumorigenesis in colon and gastric cancer. This review explores and summarizes the current views on how LL-37 contributes to immunity, pathophysiology and cell signaling involved in malignant tumor growth.
Bactericidal synergism between phage endolysin Ply2660 and cathelicidin LL-37 against vancomycin-resistant Enterococcus faecalis biofilms.
Antibiotic resistance and the ability to form biofilms of Enterococcus faecalis have compromised the choice of therapeutic options, which triggered the search for new therapeutic strategies, such as the use of phage endolysins and antimicrobial peptides. However, few studies have addressed the synergistic relationship between these two promising options. Here, we investigated the combination of the phage endolysin Ply2660 and the antimicrobial peptide LL-37 to target drug-resistant biofilm-producing E. faecalis. In vitro bactericidal assays were used to demonstrate the efficacy of the Ply2660-LL-37 combination against E. faecalis. Larger reductions in viable cell counts were observed when Ply2660 and LL-37 were applied together than after individual treatment with either substance. Transmission electron microscopy revealed that the Ply2660-LL-37 combination could lead to severe cell lysis of E. faecalis. The mode of action of the Ply2660-LL-37 combination against E. faecalis was that Ply2660 degrades cell wall peptidoglycan, and subsequently, LL-37 destroys the cytoplasmic membrane. Furthermore, Ply2660 and LL-37 act synergistically to inhibit the biofilm formation of E. faecalis. The Ply2660-LL-37 combination also showed a synergistic effect for the treatment of established biofilm, as biofilm killing with this combination was superior to each substance alone. In a murine peritoneal septicemia model, the Ply2660-LL-37 combination distinctly suppressed the dissemination of E. faecalis isolates and attenuated organ injury, being more effective than each treatment alone. Altogether, our findings indicate that the combination of a phage endolysin and an antimicrobial peptide may be a potential antimicrobial strategy for combating E. faecalis.
LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants.
Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.
The Roles of Cathelicidin LL-37 in Inflammatory Bowel Disease.
Human cathelicidin LL-37, the only member of the cathelicidin family of host defense peptides expressed in humans, plays a crucial role in host defense against pathogen invasion, as well as in regulating the functions of anti-inflammation, antitumorigenesis, and tissue repair. It is primarily produced by phagocytic leukocytes and epithelial cells, and mediates a wide range of biological responses. Emerging evidence from several studies indicates that LL-37 plays a prominent and complex role in inflammatory bowel disease (IBD). Although overexpression of LL-37 has been implicated in the inflamed and noninflamed colon mucosa in patients with ulcerative colitis, LL-37 expression was not changed in the inflamed or noninflamed colon or ileal mucosa in patients with Crohn's disease. Furthermore, studies in animal models and human patients further characterized the protective effect of cathelicidins both in ulcerative colitis and Crohn's disease. These data suggest the intricate functions of LL-37 in IBD. They will also create many strategies and opportunities for therapeutic intervention in IBD in the future. This review aims to elucidate the structure and bioactivity of LL-37 and also discuss the recent progress in understanding the relationship between LL-37 and IBD.
Positive correlations between hCAP18/LL-37 and chondroitin sulphate levels in chronic periodontitis.
To measure the levels of hCAP18/LL-37 in gingival crevicular fluid from patients with periodontal diseases compared with healthy controls and to determine the correlation between hCAP18/LL-37 and chondroitin sulphate (CS) levels in patients with periodontitis. Gingival crevicular fluid samples from 51 patients and 25 healthy volunteers were analysed for the hCAP18/LL-37 levels by immunoblotting and were determined for the CS levels by the competitive enzyme-linked immunosorbent assay. Tris buffer pH 9.85 was selected to recover hCAP18/LL-37 from Periopaper strips, in which the percentages of recovery were around 70%. The median levels of hCAP18/LL-37 in the aggressive and the chronic periodontitis (CP) groups were significantly greater than those in the gingivitis and the healthy groups (p < 0.05). Significant correlations between the unprocessed 18-kDa fragment and CS levels (r = 0.650; p < 0.001) and between the mature 4.6-kDa fragment and CS levels (r = 0.502; p < 0.001) were observed only in the CP group. The significant correlations between the hCAP18/LL-37 and the CS levels were found in CP, but not in aggressive periodontitis. The presence versus absence of such correlations may be clinically applicable to help clinicians distinguish between two distinct types of periodontitis.
The host and the flora.
To prevent bacterial overgrowth, colonization of the epithelium and subsequent translocation, the gastrointestinal tract maintains an effective mucosal barrier. Besides mucus the most important components of this protective system are epithelial antimicrobial peptides such as defensins, the cathelicidin LL-37, lysozyme, phospholipase A, and proteins with additional antimicrobial properties such as ubiquicidin, ribosomal proteins or histones. Commensal species may tolerate intestinal antimicrobial peptides, for example Bacteroides ssp. or Parabacteroides ssp. as major species in the human colon were highly resistant to the constitutive defensin HBD-1 and only susceptible to the inducible defensin HBD-3. Reduction of disulfide bonds is an important mechanism activating HBD-1. As several studies show, alterations in the expression of antimicrobial peptides directly influence the composition of the intestinal flora. Correspondingly, an increased production of defensins or inhibition of the processing of mouse defensins to their active form led to a quantitative shift of luminal and mucosal bacterial species. On the other hand, microorganisms also modulate the synthesis of host defensins by induction or inhibition of specific peptides. Lactobacilli, the probiotic strain Escherichia coli Nissle and Salmonella enteritica stimulate HBD-2 expression, whereas Shigella flexneri downregulates the synthesis of HBD-1, HBD-3 and LL-37. Thus, the proper balance between the luminal flora and the mucosa is a permanently dynamic, sensitive and host-specific relationship.
Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer.
LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.
Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications.
Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects.
Cathelicidin LL-37 Expression in Human Breast Implant Capsules.
Capsular contracture is the most common complication following breast implant placement. Cathelicidin LL-37 is a cationic peptide involved in innate immunity. Initially investigated for its antimicrobial role, it was found to have pleiotropic activities, such as immunomodulation, angiogenesis stimulation, and tissue healing. The aim of the study was to investigate the expression and localization of LL-37 in human breast implant capsules and its relationship with capsular formation, remodeling, and clinical outcomes. The study enrolled 28 women (29 implants) who underwent expander substitution with definitive implant. Contracture severity was evaluated. Specimens were stained with hematoxylin and eosin, Masson trichrome, immunohistochemistry, and immunofluorescence for LL-37, CD68, α-smooth muscle actin, collagen type I and type III, CD31, and Toll-like receptor-4. LL-37 was expressed in macrophages and myofibroblasts of capsular tissue in 10 (34%) and nine (31%) of the specimens, respectively. In eight cases (27.5%), it was expressed by both macrophages and myofibroblasts of the same specimen. In infected capsules, expression by both cell types was found in all (100%) specimens. LL-37 expression by myofibroblasts positively correlated with its expression by macrophages ( P < 0.001). Moreover, LL-37 expression by macrophages of periexpander capsules negatively correlated with the severity of capsular contracture on definitive implants ( P = 0.04). This study demonstrates the expression of LL-37 in macrophages and myofibroblasts of capsular tissue and its negative correlation with the severity of capsular contracture following permanent implant placement. Expression or up-regulation of LL-37 may be involved in myofibroblast and macrophage modulation, thus playing a role in the pathogenic fibrotic process underlying capsular contracture. This is the first study to demonstrate LL37 expression in capsular tissue and to hypothesize its role in contracture and as a prognostic marker for contracture severity. If confirmed, medical strategies or implant coating could be implemented to reduce the risk of contracture for high-risk patients.
Antimicrobial peptides in 2014.
This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.
Antifungal properties of cathelicidin LL-37: current knowledge and future research directions.
The threat of fungal diseases is substantially underestimated worldwide, but they have serious consequences for humans, animals, and plants. Given the limited number of existing antifungal drugs together with the emergence of drug-resistant strains, many researchers have actively sought alternatives or adjuvants to antimycotics. The best way to tackle these issues is to unearth potential antifungal agents with new modes of action. Antimicrobial peptides are being hailed as a promising source of novel antimicrobials since they exhibit rapid and broad-spectrum microbicidal activities with a reduced likelihood of developing drug resistance. Recent years have witnessed an explosion in knowledge on microbicidal activity of LL-37, the sole human cathelicidin. Herein, we provide a summary of the current understanding about antifungal properties of LL-37, with particular emphasis on its molecular mechanisms. We further illustrate fruitful areas for future research. LL-37 is able to inhibit the growth of clinically and agronomically relevant fungi including Aspergillus, Candida, Colletotrichum, Fusarium, Malassezia, Pythium, and Trichophyton. Destruction of the cell wall integrity, membrane permeabilization, induction of oxidative stress, disruption of endoplasmic reticulum homeostasis, formation of autophagy-like structures, alterations in expression of numerous fungal genes, and inhibition of cell cycle progression are the key mechanisms underlying antifungal effects of LL-37. Burgeoning evidence also suggests that LL-37 may act as a potential anti-virulence peptide. It is hoped that this review will not only motivate researchers to conduct more detailed studies in this field, but also inspire further innovations in the design of LL-37-based drugs for the treatment of fungal infections.
Gingival crevicular fluid and serum hCAP18/LL-37 levels in generalized aggressive periodontitis.
hCAP18/LL-37 is an endogenous antibiotic having a role in innate immunity. The aim of the present study was to evaluate serum and gingival crevicular fluid (GCF) hCAP18/LL-37 levels in patients with generalized aggressive periodontitis (G-AgP). Twenty-six G-AgP patients, 24 gingivitis patients, and 25 healthy subjects were included in this study. Periodontal parameters including probing depth, clinical attachment level, plaque index, and papilla bleeding index were recorded. GCF and serum hCAP18/LL-37 levels were analyzed by enzyme-linked immunosorbent assay. GCF hCAP18/LL-37 level was significantly higher in G-AgP compared to others (p = 0.038, p < 0.001). Gingivitis patients had significantly higher GCF hCAP18/LL-37 levels than controls (p < 0.001). No significant differences were observed in serum hCAP18/LL-37 levels among the study groups (p = 0.524). While there were positive correlations between GCF hCAP18/LL-37 levels and periodontal parameters of sampling sites (p < 0.005), no significant correlation was observed between serum hCAP18/LL-37 levels and whole-mouth periodontal parameters (p > 0.05). Increased levels of GCF hCAP18/LL-37 in G-AgP might show that it is abundantly expressed in the presence of periodontal tissue destruction. Serum hCAP18/LL-37 levels do not seem to be related with the presence of G-AgP. hCAP18/LL-37 antimicrobial peptide might be associated with periodontal tissue destruction in the presence of aggressive periodontitis.
Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis.
COVID-19 is characterized by hyperactivation by inflammatory cytokines and recruitment of macrophages, neutrophils, and other immune cells, all hallmarks of a strong inflammatory response that can lead to severe complications and multi-organ damage. Mortality in COVID-19 patients is associated with a high prevalence of neutrophil extracellular trap (NET) formation and microthrombosis that are exacerbated by hyperglycemia, diabetes, and old age. SARS-CoV-2 infection in humans and non-human primates have revealed long-term neurological consequences of COVID-19, possibly concomitant with the formation of Lewy bodies in the brain and invasion of the nervous system via the olfactory bulb. In this paper, we review the relevance of the human cathelicidin LL-37 in SARS-CoV-2 infections. LL-37 is an immunomodulatory, host defense peptide with direct anti-SARS-CoV-2 activity, and pleiotropic effects on the inflammatory response, neovascularization, Lewy body formation, and pancreatic islet cell function. The bioactive form of vitamin D and a number of other compounds induce LL-37 expression and one might predict its upregulation, could reduce the prevalence of severe COVID-19. We hypothesize upregulation of LL-37 will act therapeutically, facilitating efficient NET clearance by macrophages, speeding endothelial repair after inflammatory tissue damage, preventing α-synuclein aggregation, and supporting blood-glucose level stabilization by facilitating insulin release and islet β-cell neogenesis. In addition, it has been postulated that LL-37 can directly bind the S1 domain of SARS-CoV-2, mask angiotensin converting enzyme 2 (ACE2) receptors, and limit SARS-CoV-2 infection. Purposeful upregulation of LL-37 could also serve as a preventative and therapeutic strategy for SARS-CoV-2 infections.
Engineered Exosomes Containing Cathelicidin/LL-37 Exhibit Multiple Biological Functions.
Exosomes show great potential in diagnostic and therapeutic applications. Inspired by the human innate immune defense, herein, we report engineered exosomes derived from monocytic cells treated with immunomodulating compounds 1α,25-dihydroxyvitamin D3, and CYP24A1 inhibitor VID400 which are slowly released from electrospun nanofiber matrices. These engineered exosomes contain significantly more cathelicidin/LL-37 when compared with exosomes derived from either untreated cells or Cathelicidin Human Tagged ORF Clone transfected cells. In addition, such exosomes exhibit multiple biological functions evidenced by killing bacteria, facilitating human umbilical vein endothelial cell tube formation, and enhancing skin cell proliferation and migration. Taken together, the engineered exosomes developed in this study can be used as therapeutics alone or in combination with other biomaterials for effective infection management, wound healing, and tissue regeneration.
Cathelicidin (LL-37) causes expression of inflammatory factors in coronary artery endothelial cells of Kawasaki disease by activating TLR4-NF-κB-NLRP3 signaling.
Kawasaki disease (KD) is a type of vasculitis with an unidentified etiology. Cathelicidin (LL-37) may be involved in the development of the KD process; therefore, further research to investigate the molecular mechanism of LL-37 involvement in KD is warranted. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, NLRP3, and LL-37 in the sera of healthy subjects, children with KD, and children with pneumonia. Subsequently, human recombinant LL-37 or/and toll-like receptors 4 (TLR4)-specific inhibitor TAK-242 stimulated human coronary artery endothelial cells (HCAECs), CCK-8 was used to detect cell proliferation, flow cytometry to detect apoptosis, transmission electron microscopy to observe cytoskeletal changes, Transwell to measure cell migration ability, ELISA to detect inflammatory factor levels, Western blot analysis to analyze protein levels of toll-like receptors 4 (TLR4) and NF-κB p-65, and quantitative real-time polymerase chain reaction (qRT-PCR) to determine LL-37, NLRP3 mRNA levels. In this study, we found that the level of LL-37 was highly expressed in the serum of children with KD, and after LL-37 stimulation, apoptosis was significantly increased in HCAECs, and the expression levels of TLR4, NLRP3 and inflammatory factors in cells were significantly enhanced. Intervention with the TLR4-specific inhibitor TAK-242 significantly alleviated the LL-37 effects on cellular inflammation, TLR4, NLRP3 promotion effect. Our data suggest that LL-37 induces an inflammatory response in KD coronary endothelial cells via TLR4-NF-κB-NLRP3, providing a potential target for the treatment of KD.
Cathelicidin LL-37-ApoB-100 interaction promotes LDL clearance and attenuates cholesterol accumulation in the liver.
Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe-/- mice with hypercholesterolemia, the murine homolog cathelicidin Cramp similarly accelerates cholesterol clearance by activating cholesterol excretion and preventing hepatic lipid accumulation. This study identifies LL-37 as an endogenous regulator of LDL that promotes LDL cholesterol clearance.
The human cathelicidin LL-37--A pore-forming antibacterial peptide and host-cell modulator.
The human cathelicidin hCAP18/LL-37 has become a paradigm for the pleiotropic roles of peptides in host defence. It has a remarkably wide functional repertoire that includes direct antimicrobial activities against various types of microorganisms, the role of 'alarmin' that helps to orchestrate the immune response to infection, the capacity to locally modulate inflammation both enhancing it to aid in combating infection and limiting it to prevent damage to infected tissues, the promotion of angiogenesis and wound healing, and possibly also the elimination of abnormal cells. LL-37 manages to carry out all its reported activities with a small and simple, amphipathic, helical structure. In this review we consider how different aspects of its primary and secondary structures, as well as its marked tendency to form oligomers under physiological solution conditions and then bind to molecular surfaces as such, explain some of its cytotoxic and immunomodulatory effects. We consider its modes of interaction with bacterial membranes and capacity to act as a pore-forming toxin directed by our organism against bacterial cells, contrasting this with the mode of action of related peptides from other species. We also consider its different membrane-dependent effects on our own cells, which underlie many of its other activities in host defence. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.
β-Amyloid (Aβ) and Human Cathelicidin LL-37: Two Sides of the Same Coin?
Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer's disease (AD), it may initially be beneficial at the onset of infection. As an evolutionary conserved antimicrobial peptide (AMP), Aβ contributes to innate immune defense against pathogens. Host defense peptides such as Aβ and human cathelicidin (LL-37) not only kill pathogens through their antimicrobial activity but also exhibit high affinity for bacterial lipopolysaccharides (LPSs) and membrane receptors. LL-37, which is upregulated in the brain, binds to Aβ, modulating its aggregation; Aβ and LL-37 are protective under physiological conditions, but during chronic infection or dysregulation, their interaction becomes toxic and contributes to AD pathology. Similarly to Aβ, LL-37 can induce neuroinflammation by stimulating human microglia to release inflammatory cytokines, such as TNF-α and IL-6. Neuroinflammation is essential for protecting the brain from pathogens-when prolonged, it drives pathological processes underlying AD, Parkinson's disease (PD), and other neurodegenerative disorders.
Cathelicidin LL-37: A new important molecule in the pathophysiology of systemic lupus erythematosus.
Cathelicidin LL-37 is an antimicrobial peptide that is synthesized by epithelial cells, neutrophils, or lymphocytes and act as an essential defense mechanism against bacterial, viral, or fungi infection of eukaryotic organisms. However, in recent years, this cathelicidin has gained the interest of the scientific community because, besides its antimicrobial properties, LL-37 is an immunomodulator that can contribute to the development of autoimmune diseases. The other non-antimicrobial function of this cathelicidin is its ability to form complexes with the DNA, stimulating plasmacytoid dendritic cells (pDCs) to produce type I IFN, deciding the course of autoimmune diseases, including systemic lupus erythematosus (SLE). The chronic activation of pDCs by surrounding complexes is a crucial factor for the early development of autoimmunity in SLE patients. This stimulation is given by the complexes (LL-37-DNA/anti-DNA) recognized by the receptor FcγRII on pDCs, allowing its endocytosis and its recognition via TLR9, leading to the activation of pDCs and enhanced type I IFN production. In this article, we reviewed the structure, function, and importance of LL-37 in innate immunity, as well as its biological plausibility in the pathophysiology of autoimmune diseases such as SLE. In this narrative review, we included primary journal articles describing the function, structure, prevalence, and importance of LL-37 in various manifestations of SLE, as well as LL-37 and anti-LL37 antibodies in patients with SLE or other autoimmune diseases. In conclusion, LL-37 is an essential molecule in the pathophysiology of SLE, mainly by its role in increasing the production of IFN by pDCs, which postulates it as a crucial molecule in the pathophysiology of SLE and, given plausibility biology, could serve as a biomarker of the disease.
Design of Antimicrobial Peptides: Progress Made with Human Cathelicidin LL-37.
The incorporation of the innate immune system into humans is essential for survival and health due to the rapid replication of invading microbes and the delayed action of the adaptive immune system. Antimicrobial peptides are important components of human innate immunity. Over 100 such peptides have been identified in various human tissues. Human cathelicidin LL-37 is best studied, and there has been a growing interest in designing new peptides based on LL-37. This chapter describes the alternative processing of the human cathelicidin precursor, protease digestion, and lab cutting of LL-37. Both a synthetic peptide library and structure-based design are utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region. The minimal region of LL-37 can be function-dependent. We discuss the design and potential applications of LL-37 into antibacterial, antibiofilm, antiviral, antifungal, immune modulating, and anticancer peptides. LL-37 has been engineered into 17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. Both 17BIPHE2 and SAAP-148 can eliminate the ESKAPE pathogens and show topical in vivo antibiofilm efficacy. Also discussed are other application strategies, including peptide formulation, antimicrobial implants, and peptide-inducing factors such as vitamin D and sunlight. Finally, we summarize what we learned from peptide design based on human LL-37.
Nanoantibiotics containing membrane-active human cathelicidin LL-37 or synthetic ceragenins attached to the surface of magnetic nanoparticles as novel and innovative therapeutic tools: current status and potential future applications.
Nanotechnology-based therapeutic approaches have attracted attention of scientists, in particular due to the special features of nanomaterials, such as adequate biocompatibility, ability to improve therapeutic efficiency of incorporated drugs and to limit their adverse effects. Among a variety of reported nanomaterials for biomedical applications, metal and metal oxide-based nanoparticles offer unique physicochemical properties allowing their use in combination with conventional antimicrobials and as magnetic field-controlled drug delivery nanocarriers. An ever-growing number of studies demonstrate that by combining magnetic nanoparticles with membrane-active, natural human cathelicidin-derived LL-37 peptide, and its synthetic mimics such as ceragenins, innovative nanoagents might be developed. Between others, they demonstrate high clinical potential as antimicrobial, anti-cancer, immunomodulatory and regenerative agents. Due to continuous research, knowledge on pleiotropic character of natural antibacterial peptides and their mimics is growing, and it is justifying to stay that the therapeutic potential of nanosystems containing membrane active compounds has not been exhausted yet.
Tissue-specific Regulation of Innate Immune Responses by Human Cathelicidin LL-37.
Cathelicidins form one of the major families of antimicrobial peptides and have been identified in many vertebrates, including humans. LL-37, the only human member of the cathelicidin family, is detected in most sites of the human body that is normally exposed to microbes, including the epithelial lining of the skin, gastrointestinal tract, genitourinary tract and lungs. This peptide is also expressed by a variety of epithelial cells and immune cells, such as neutrophils, monocytes and mast cells. LL-37 has emerged as a key component of innate immunity due to its direct antimicrobial activity against a broad spectrum of invading pathogens. It also exhibits diverse immunomodulatory functions by activating both pro- and anti-inflammatory mediators; inducing cell migration, proliferation and differentiation; and regulating apoptosis of epithelial cells and neutrophils. Given that the phenotypic and functional properties of immune compartments are different and significantly impacted by the anatomical sites, tissue-specific factors of host origin and microbial communities play important roles in the regulation of LL-37. This review summarizes the expression and biological functions of LL-37 and discusses its significant roles in the innate immune system based on its anatomical distribution.
Human Cathelicidin Peptide LL-37 Induces Cell Death in Autophagy-Dysfunctional Endothelial Cells.
Human cathelicidin LL-37 is an antimicrobial peptide that has a broad spectrum of antimicrobial activities but also acts on host cells to exert immunomodulatory functions. It has been suggested that the increase of LL-37 in atherosclerotic aortas and the dysregulated autophagy of endothelial cells are involved in the pathogenesis of atherosclerosis. In this study, to elucidate the role of LL-37 in atherosclerosis, we investigated the effect of LL-37 on autophagy in endothelial cells using HUVECs. First, LL-37 upregulated LC3-II (an autophagosomal membrane marker) and enhanced the formation of LC3-positive puncta in the cells, suggesting that LL-37 induces autophagy in endothelial cells. Second, LL-37 was associated with p62, which recognizes ubiquitinated proteins and transfers them to autophagosomes, suggesting that LL-37 is ubiquitinated and recognized by p62. Third, the degradation of LL-37 was delayed, and LL-37 induced cell death in atg7 knockdown cells, which was accompanied by the formation of protein aggregates in the cells. Taken together, these observations suggest that LL-37 induces autophagy in endothelial cells but enhances cell death in autophagy-dysfunctional conditions, in which the intracellular degradation of LL-37 is disturbed. Thus, LL-37 may exert an adverse action on autophagy-dysfunctional endothelial cells to induce cell death in the pathogenesis of atherosclerosis.
The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium.
Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.
Cathelicidin LL-37 promotes wound healing in diabetic mice by regulating TFEB-dependent autophagy.
Diabetic patients often experience impaired wound healing. Human cathelicidin LL-37 possesses various biological functions, such as anti-microbial, anti-inflammatory, and pro-wound healing activities. Autophagy has important effects on skin wound healing. However, little is known about whether LL-37 accelerates diabetic wound healing by regulating autophagy. In the study, we aimed to investigate the role of autophagy in LL-37-induced wound healing and uncover the underlying mechanisms involved. A full-thickness wound closure model was established in diabetic mice to evaluate the effects of LL-37 and an autophagy inhibitor (3-MA) on wound healing. The roles of LL-37 and 3-MA in regulating keratinocyte migration were assessed using transwell migration and wound healing assays. The activation of transcription factor EB (TFEB) was measured using western blotting and immunofluorescence (IF) assays of its nuclear translocation. The results showed that LL-37 treatment improved wound healing in diabetic mice, whereas these effects were reversed by 3-MA. In vitro, 3-MA decreased the effects of LL-37 on promoting HaCat keratinocyte migration in the presence of high glucose (HG). Mechanistically, LL-37 promoted TFEB activation and resulted in subsequent activation of autophagy, as evidenced by increased nuclear translocation of TFEB and increased expression of ATG5, ATG7, and beclin 1 (BECN1), whereas these changes were blocked by TFEB knockdown. As expected, TFEB knockdown damaged the effects of LL-37 on promoting keratinocyte migration. Collectively, these results suggest that LL-37 accelerates wound healing in diabetic mice by activating TFEB-dependent autophagy, providing new insights into the mechanism by which LL-37 promotes diabetic wound healing.
Significance of the LL-37 Peptide Delivered from Human Cathelicidin in the Pathogenesis, Treatment, and Diagnosis of Sepsis.
Antimicrobial peptides, which function as the first line of host immune defense, have recently been identified as important immunomodulators of inflammation, and are involved as regulatory molecules in infections, including sepsis. Treatment of sepsis is very complex and remains largely challenging and sometimes ineffective. This creates a need to develop new therapeutic strategies focusing not only on the elimination of sepsis-causing microorganisms, which can be achieved with antibiotics, but also on the control of the immune system and its overactive response resulting in increased vascular endothelial permeability. One approach to develop new treatments for patients with sepsis is to better understand the pleiotropic function of the human LL-37 peptide that originates from the human cathelicidin antibacterial protein (h-CAP18). An increasing number of studies indicate high dynamics of changes in LL-37 concentration in the blood during sepsis. Additionally, in animal models, administration of exogenous LL-37 peptide to mice with experimentally induced sepsis increases their survival. It can therefore be assumed that knowledge of the molecular mechanism of cathelicidin LL-37 action, as well as the synthesis of its stable analogs, will result in progress in the diagnosis and therapy of sepsis.
Human cathelicidin LL-37 rapidly disrupted colonic epithelial integrity.
The intestinal barrier, held together by epithelial cells and intercellular tight junction (TJ) proteins, prevents the penetration of microbial pathogens. Concurrently, intestinal epithelial cells secrete antimicrobial peptides, including cathelicidin. Cathelicidin has direct antibacterial and immunomodulatory functions, although its role in intestinal integrity remains elusive. In this study, we demonstrate that direct stimulation of human colonic epithelial (T84) cells with human cathelicidin, LL-37, resulted in a rapid and transient increase in epithelial cell permeability. This increased permeability was associated with the TJ proteins occludin and claudin-2 degradation, mediated by these specific proteins' endocytosis and lysosomal degradation. While murine cathelicidin (CRAMP) failed to modify T84 cell permeability, LL-37 degraded TJ proteins in murine rectal epithelial (CMT-93) cells. The stimulus of (CMT-93) cells with LL-37 aggravated the cell permeability and furthered TJ degradation provoked by the intestinal pathogen, attaching/effacing (A/E) Citrobacter rodentium (C. rodentium). The number of C. rodentium that colonized CMT-93 cells was not severely impacted by the presence of LL-37. While a temporary disruption of tight junctions by LL-37 may lead to a 'leaky gut,' this study demonstrates that LL-37 increases epithelial cell permeability by degrading TJ proteins occludin and claudin-2 through endocytosis and lysosomal degradation. These immunomodulatory actions occurring at concentrations lower than those microbicidal uncover a new guise for cathelicidin modulating the epithelial barrier against A/E pathogens. Recognizing native cathelicidin's functions in a specified disease setting (e.g., colitis) will help establish it as an anti-infectious immunomodulator.
The Human Cathelicidin Antimicrobial Peptide LL-37 and Mimics are Potential Anticancer Drugs.
Antimicrobial peptides (AMPs) play a critical role in innate host defense against microbial pathogens in many organisms. The human cathelicidin, LL-37, has a net positive charge and is amphiphilic, and can eliminate pathogenic microbes directly via electrostatic attraction toward negatively charged bacterial membranes. A number of studies have shown that LL-37 participates in various host immune systems, such as inflammatory responses and tissue repair, in addition to its antibacterial properties. Moreover, recent evidence suggests that it is also involved in the regulation of cancer. Indeed, previous studies have suggested that human LL-37 is involved in carcinogenesis via multiple reporters, such as FPR2 (FPRL1), epidermal growth factor receptor, and ERBb2, although LL-37 and its fragments and analogs also show anticancer effects in various cancer cell lines. This discrepancy can be attributed to peptide-based factors, host membrane-based factors, and signal regulation. Here, we describe the association between AMPs and cancer with a focus on anticancer peptide functions and selectivity in an effort to understand potential therapeutic implications.
Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway.
Rosacea is a chronic inflammatory disease of facial skin with unknown pathophysiology. Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea. However, its significance in rosacea pathogenesis is not fully understood. We sought to understand the molecular mechanisms of LL-37-mediated rosacea-like inflammation in an in vitro model of normal human epidermal keratinocytes. Transcriptome profiling of LL-37-treated keratinocytes identified signatures of IFN-stimulating genes, such as CXCL10, IFIT2, RSAD2, and CXCL11 among the top upregulated differentially expressed genes. Gene ontology enrichment of biological processes revealed activation of cellular response to molecules of bacterial origin, response to chemokines, and cytokine-mediated signaling pathways, whereas Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed the activation of TNF signaling, IL-17 signaling, NF-kB signaling, and chemokine signaling among the most significant pathways. Remarkably, T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure. Mechanistically, LL-37-induced CXCL10 production relied on the Jak1/signal transducer and activator of transcription 1 signaling pathway. In summary, our findings provide a crucial link to keratinocyte-T-cell crosstalk, and blockade of the CXCL10:CXCR3 axis or Jak1/signal transducer and activator of transcription 1 pathways can be an effective anti-inflammatory strategy to reduce rosacea inflammation by restricting pathogenic T-cell infiltration.
Between good and evil: Complexation of the human cathelicidin LL-37 with nucleic acids.
The innate immune system provides a crucial first line of defense against invading pathogens attacking the body. As the only member of the human cathelicidin family, the antimicrobial peptide LL-37 has been shown to have antiviral, antifungal, and antibacterial properties. In complexation with nucleic acids, LL-37 is suggested to maintain its beneficial health effects while also acting as a condensation agent for the nucleic acid. Complexes formed by LL-37 and nucleic acids have been shown to be immunostimulatory with a positive impact on the human innate immune system. However, some studies also suggest that in some circumstances, LL-37/nucleic acid complexes may be a contributing factor to autoimmune disorders such as psoriasis and systemic lupus erythematosus. This review provides a comprehensive discussion of research highlighting the beneficial health effects of LL-37/nucleic acid complexes, as well as discussing observed detrimental effects. We will emphasize why it is important to investigate and elucidate structural characteristics, such as condensation patterns of nucleic acids within complexation, and their mechanisms of action, to shed light on the intricate physiological effects of LL-37 and the seemingly contradictory role of LL-37/nucleic acid complexes in the innate immune response.
The roles of cathelicidin LL-37 in immune defences and novel clinical applications.
LL-37 is the only member of the cathelicidin family of host defence peptides expressed in humans. It is primarily produced by phagocytic leucocytes and epithelial cells, and mediates a wide range of biological responses: direct killing of microorganisms, chemotaxis and chemokine induction, regulation of inflammatory responses, as well as adjuvant, angiogenic and wound healing effects. In this review we will cover the recent advances in the understanding of LL-37 biology: its activities, the mechanisms of its induction and roles in immune defence. Recent studies advanced our understanding of the mechanisms controlling LL-37 expression, demonstrating the key involvement of the vitamin D3 and the hypoxia response pathways, and the impacts of commensal and pathogenic microorganisms on its production. The synergistic and antagonistic interactions between LL-37 and other immune mediators have been further elucidated. Furthermore, studies in animal models and human patients further characterized the roles of cathelicidins in immunity, with roles in infectious and inflammatory conditions. The underlying properties of LL-37 have been exploited to create innate defence regulator peptides that represent a novel immunomodulatory approach to treating infections. The understanding of the biological properties and functions of LL-37 and other host defence peptides advances our knowledge of innate immunity, the interactions of the host with pathogens and the microflora, as well as the pathology of infectious and inflammatory diseases, creating many strategies and opportunities for therapeutic intervention.
CXCR2 specific endocytosis of immunomodulatory peptide LL-37 in human monocytes and formation of LL-37 positive large vesicles in differentiated monoosteophils.
Immunomodulatory peptide cathelicidin/LL-37 induces human monocyte differentiation into a novel bone repair cell, the monoosteophil. We now demonstrate that LL-37 is endocytosed by monocytes over a period of 6 days producing large (10 × 2 μm), specialized LL-37 and integrin α3 positive vesicles. CXCR2, a membrane receptor previously associated with the binding of LL-37 to neutrophils, was co-endocytosed with LL-37 where both markers remained within the cytosol over a 16 h observation period. Endocytosis of LL-37 was mediated by a clathrin- and cavoelin/lipid raft-dependent pathway into early Rab5+ endosomes expressing APPL1 and EEA1. From 4 to 16 h, LL-37 vesicles co-localized with the Golgi, mitochondria, and to a lesser extent lysosomes and ER. By day 6, LL-37 was associated with large (>10 μm) vesicles, adjacent to Golgi, mitochondria, ER and lysosomes. LL-37 co-stained with integrin α3, tetraspanin CD9, GPI-linked CD59 and costimulatory molecule CD276 (B7-H3) in these vesicles. Continuous tracking of LL-37 with its associated vesicles over 6 days indicates that LL-37 is an extremely stable, membrane-associated peptide that plays a critical role in the differentiation of monocytes into monoosteophils.
Quick links (PubMed)
- PMID 38642493 — 2024 · Vitamin D triggers hCAP18/LL-37 production: Implications for LL-37-induc…
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- PMID 36781570 — 2023 · Antibiofilm properties of cathelicidin LL-37: an in-depth review.
- PMID 26434733 — 2015 · Unique features of human cathelicidin LL-37.
- PMID 17028774 — 2007 · Recombinant expression of human cathelicidin (hCAP18/LL-37) in Pichia pa…
- PMID 20049649 — 2010 · Cathelicidin LL-37: a multitask antimicrobial peptide.
- PMID 17655171 — 2007 · Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide.
- PMID 26395996 — 2016 · The Role of Cathelicidin LL-37 in Cancer Development.
- PMID 37024490 — 2023 · Bactericidal synergism between phage endolysin Ply2660 and cathelicidin …
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- PMID 27135484 — 2016 · The Roles of Cathelicidin LL-37 in Inflammatory Bowel Disease.
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- PMID 29843147 — 2018 · Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer.
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- PMID 38057654 — 2023 · Antifungal properties of cathelicidin LL-37: current knowledge and futur…
- PMID 27129587 — 2017 · Gingival crevicular fluid and serum hCAP18/LL-37 levels in generalized a…
- PMID 35634307 — 2022 · Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression M…
- PMID 35930707 — 2022 · Engineered Exosomes Containing Cathelicidin/LL-37 Exhibit Multiple Biolo…
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- PMID 40971038 — 2026 · Cathelicidin LL-37-ApoB-100 interaction promotes LDL clearance and atten…
- PMID 26556394 — 2016 · The human cathelicidin LL-37--A pore-forming antibacterial peptide and h…
- PMID 42353177 — 2026 · β-Amyloid (Aβ) and Human Cathelicidin LL-37: Two Sides of th…
- PMID 32743514 — 2020 · Cathelicidin LL-37: A new important molecule in the pathophysiology of s…
- PMID 30980360 — 2019 · Design of Antimicrobial Peptides: Progress Made with Human Cathelicidin …
- PMID 31898542 — 2020 · Nanoantibiotics containing membrane-active human cathelicidin LL-37 or s…
- PMID 29589544 — 2018 · Tissue-specific Regulation of Innate Immune Responses by Human Cathelici…
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