LL-37

What is LL-37?#

LL-37 is a peptide that has been studied in preclinical and clinical research models for its potential therapeutic properties.

Mechanism of Action#

LL-37 is a cationic, amphipathic host-defense peptide that acts through multiple membrane and intracellular mechanisms to coordinate antimicrobial defense, inflammation, and tissue repair. Its pleiotropy reflects engagement of distinct receptor classes and membrane-coupled processes that converge on MAPKs, PI3K–Akt, ROS/NADPH oxidase, NF-κB, and inflammasome pathways.

Primary receptors and membrane mechanisms

• Formyl peptide receptor 2 (FPR2/ALX; GPCR). LL-37 functions as an FPR2 agonist on myeloid and epithelial cells, triggering Gi-dependent PLC activation, Ca2+ mobilization, ERK and p38 MAPK, PI3K/Akt, and NADPH oxidase–derived ROS. These signals drive chemotaxis, respiratory burst, leukotriene production, NET formation, survival, and angiogenesis; cross-talk with RTKs can occur downstream (e.g., transactivation).
• CXCR2 (chemokine receptor; GPCR). Evidence supports LL-37 as a functional CXCR2 ligand in neutrophils/monocytes, eliciting Ca2+ mobilization, ERK and PI3K signaling, chemotaxis, and angiogenic responses; CXCR2-mediated endocytosis of LL-37 has been observed.
• MRGPRX2/MrgprB2 (mast cell GPCR). LL-37 directly activates mast cells via MRGPRX2, engaging Gαi/Gαq, Ca2+ influx, ERK and PI3K to induce rapid degranulation and cytokine release; this axis contributes to cutaneous inflammation, itch, and rosacea-like pathology in vivo.
• P2X7 (ligand-gated ion channel). LL-37 activates P2X7 in human myeloid and epithelial cells, producing cation flux/pore formation that promotes NLRP3 inflammasome assembly, caspase‑1 activation, and IL‑1β maturation. Depending on context, LL-37 can either potentiate IL‑1β release or inhibit ATP/P2X7-driven pyroptosis and inflammasome activity, reflecting concentration- and cell-type dependence.
• EGFR transactivation (RTK). LL-37 induces triple-membrane-passing signaling: GPCR/membrane-triggered activation of an ADAM-family metalloprotease (notably ADAM17) causes shedding of pro–HB‑EGF/TGF‑α, leading to EGFR activation and downstream ERK and PI3K–Akt cascades. Consequences include epithelial proliferation, migration, mucin/chemokine induction, and wound repair.
• Toll-like receptors (TLRs). LL-37 neutralizes LPS to dampen TLR4–MyD88–NF‑κB signaling in monocytes/endothelium, but can also form complexes with self- or microbial nucleic acids that are delivered to endosomes, thereby enhancing TLR7/8/9 sensing and type I IFN programs in pDCs and keratinocytes; this duality underlies antimicrobial vigilance and contributes to autoimmunity such as psoriasis.
• Membrane/channel effects. By accumulating at membranes, LL-37 can allosterically modulate or mechanically perturb transmembrane domains and open channels such as TRPV2 and BKCa, resulting in Ca2+ influx/K+ efflux that favor migration and invasion; this non-orthosteric mode may explain broad receptor engagement and the activity of D‑enantiomers.

Downstream signaling architecture

• Early signaling: GPCR coupling (Gi/Gq) → PLC → IP3/DAG → Ca2+ release/influx; activation of ERK1/2 and p38 MAPK; PI3K–Akt; and NADPH oxidase–dependent ROS that feed forward into kinase activation and transcriptional control.
• Transactivation: ADAM metalloprotease–mediated EGFR activation integrates with GPCR outputs to reinforce ERK/PI3K pathways controlling proliferation and motility.
• Transcriptional outputs: NF‑κB and IRF activation downstream of GPCR/ROS and endosomal TLRs drive cytokines/chemokines; inflammasome assembly downstream of P2X7 yields caspase‑1–dependent IL‑1β/IL‑18.

Selected molecular targets and cell-type outcomes

• Neutrophils/monocytes: FPR2 and CXCR2 signaling produces chemotaxis, respiratory burst, eicosanoid release, and survival; LL-37 modulates adhesion via Mac‑1 and can influence NETosis.
• Mast cells: MRGPRX2-dependent degranulation and mediator release drive neurogenic inflammation, itch, and rosacea-like responses; signaling requires Gαi/Gαq, Ca2+ channels, ERK, and PI3K.
• Epithelia (airway/skin/cornea): EGFR transactivation promotes proliferation, migration, and barrier repair; LL-37 also induces chemokines and mucins via EGFR–MAPK and PI3K–Akt pathways.
• Macrophages/epithelial cells: P2X7 engagement regulates LL-37 uptake, autophagy, inflammasome activation, and IL‑1β release; LL-37 can alternatively blunt ATP/P2X7-driven pyroptosis depending on milieu.
• Dendritic cells/keratinocytes/pDCs: LL-37–nucleic acid complexes potentiate endosomal TLR7/8/9, enhancing type I IFN and shaping adaptive responses; this mechanism links injury to autoimmunity.
• Cancer and platelets: LL-37 can interface with RTKs (e.g., IGF1R/ErbB2) and Wnt/β‑catenin programs in tumors, and engages platelet GPVI signaling to promote thrombo-inflammation; these effects are context dependent.

Integration and determinants of outcome LL-37’s effects are concentration-, context-, and cell-type dependent. At epithelial and inflammatory sites, GPCR-initiated cascades, ADAM–EGFR transactivation, and purinergic signaling integrate with TLR pathways and membrane perturbation to yield either proinflammatory outputs (chemokines, IL‑1β, mast cell degranulation) or pro-resolving/repair programs (wound closure, controlled ROS, angiogenesis). The same upstream engagements can favor pathogenic outcomes when nucleic acid complexing chronically amplifies endosomal TLRs. The mechanistic plurality—orthosteric GPCR activation, indirect transactivation, ion-channel modulation, and cargo delivery—explains LL-37’s broad repertoire across innate defense, tissue repair, autoimmunity, thrombosis, and cancer biology.

Therapeutic Applications#

Therapeutic applications of LL-37 span wound healing, infectious disease immunomodulation/antiviral strategies, and early oncologic intralesional therapy. Evidence includes randomized clinical trials in chronic ulcers, a completed phase I/II intratumoral melanoma study, and controlled preclinical wound models, with additional exploratory human data in COVID-19.

Wound healing—venous leg ulcers (VLU). A multicenter, phase IIb, randomized, double-blind, placebo-controlled trial (HEAL LL-37) evaluated topical LL-37 (0.5 or 1.6 mg/mL) twice weekly for 13 weeks plus compression in hard-to-heal VLUs (N≈149). In the full cohort, complete-closure proportions were similar across arms (LL-37 0.5 mg/mL: 26.5%; LL-37 1.6 mg/mL: 24.7%; placebo: 25.3%). However, in a prespecified subgroup with larger ulcers (≥10 cm²), LL-37 0.5 mg/mL improved multiple outcomes versus placebo: complete closure 28.1% vs 8.1% (P=0.0458), healing rate per day 0.0367 vs 0.0093 (P=0.0439), ≥50% area reduction 61.9% (P=0.0294) and ≥70% reduction 47.2% (P=0.0149). Treatment was generally well tolerated; local redness/edema/warmth and adjacent-skin reactions were common but mostly mild, infections were uncommon and non-serious, and no deaths occurred (overall serious adverse events 7.4%). Prior first-in-man dosing suggested a bell-shaped response, with 0.5 mg/mL outperforming higher concentrations. (mahlapuu2021evaluationofll‐37 pages 1-2, mahlapuu2021evaluationofll‐37 pages 2-4, mahlapuu2021evaluationofll‐37 pages 8-10)

Wound healing—diabetic foot ulcers (DFU). A double-blind randomized trial tested a 0.5 mg/g LL-37 cream applied twice weekly for 4 weeks in DFU with standard care. The LL-37 arm showed consistently greater increases in the granulation index at days 7, 14, 21, and 28 (p=0.031, 0.009, 0.006, 0.037), while reductions in aerobic bacterial colonization and changes in IL-1α/TNF-α were not statistically significant. Tolerability was acceptable in the reported excerpts.

Preclinical wound repair. In a mouse pressure-ulcer model, a chitosan hydrogel encapsulating 20 μg LL-37 reduced ulcer area versus controls, with significantly smaller areas on days 11 (84.24%±0.25%), 13 (56.22%±3.91%), and 15 (48.12%±0.28%) relative to baseline, alongside increased epithelial thickness, capillary density, and upregulation of HIF-1α and VEGF-A in wound tissue. The LL-37/chitosan formulation was biocompatible in vitro, reduced LPS-stimulated TNF-α release (1–5 μg/mL), and inhibited Staphylococcus aureus growth at 5 μg/mL. These data support angiogenic and immunomodulatory contributions to healing.

Oncology—intratumoral LL-37 for melanoma. A phase I/II study of intratumoral LL-37 in stage IIIB–IVA melanoma (NCT02225366) was completed with a dose-finding objective. Publicly accessible summaries emphasize intralesional administration and safety assessment; detailed response outcomes are not available in the retrieved excerpts. Secondary sources note dermatologic local toxicities characteristic of intralesional agents; definitive efficacy conclusions cannot be drawn from available records.

COVID-19—oral LL-37 via engineered Lactococcus (cas001). A small single-arm exploratory study (n=11) administered oral L. lactis engineered to express tandem LL-37 (cas001) for 3 weeks in mild COVID-19. Investigators reported encouraging improvements in gastrointestinal, systemic, and respiratory symptoms and possible effects on nucleic acid and CT results, but the design precludes efficacy inference. Safety in rats at up to 100× the estimated clinical dose showed no toxicity; in limited human exposure no adverse reactions were reported. Pharmacokinetics showed serum LL-37 peaking at ~2 h post-gavage and returning to baseline by 6 h in animals and signal increases in volunteers. As a preprint, findings await peer-reviewed confirmation.

Context from integrative reviews. Recent reviews collate LL-37’s roles in skin inflammation and wound healing, and discuss broader cathelicidin applications and challenges (e.g., cytotoxicity at higher doses, proteolysis, formulation needs), aligning with the bell-shaped dose-response and the emphasis on delivery systems observed in clinical and preclinical studies. These contextualize translational directions but do not add independent quantitative outcomes beyond the above trials and models.

Summary of documented outcomes.

• Chronic ulcers: In VLUs, overall neutral primary analysis but significant benefits in large-ulcer subgroup at 0.5 mg/mL with acceptable local tolerability; in DFU, short-term granulation improvements without significant antimicrobial or cytokine effects.
• Preclinical skin repair: LL-37 enhances closure and angiogenesis markers in murine pressure ulcers; formulation (e.g., chitosan hydrogel) augments effect and biocompatibility.
• Oncology: Intratumoral LL-37 completed early-phase melanoma testing; publicly available data emphasize safety/dosing, with efficacy not reported in the excerpts.
• Antiviral/COVID-19: Oral LL-37 expression via probiotic vector shows exploratory safety and symptomatic signals in a small uncontrolled study; not definitive for efficacy.

Key quantitative details and dosing are summarized below for reference.

Research Evidence Quality#

Overview and scope LL-37 (human cathelicidin) has a broad preclinical literature across antimicrobial, immunomodulatory, and tissue-repair biology, but a comparatively small and heterogeneous clinical evidence base. Human studies cluster in topical wound care, host-directed induction strategies (vitamin D, phenylbutyrate), small exploratory COVID-19 interventions, and a very small oncology microtrial. Larger, late-phase, placebo-controlled trials directly administering LL-37 are lacking, and some initiated studies have not yielded published results. Below we summarize the extent and quality of evidence and key limitations.

Clinical evidence: extent and rigor

• Chronic wounds (topical LL-37): A randomized, double-blind, controlled single-center trial in diabetic foot ulcers (DFU; 25 randomized: 13 LL-37, 12 placebo) found faster granulation with LL-37 over 4 weeks; bacterial colonization trends favored LL-37 until day 21; cytokines did not differ. Safety appeared acceptable; follow-up was short and sample size small (single center). Trial registered as NCT04098562 (phase noted as II by registry).
• Venous leg ulcers: A prior randomized, placebo-controlled, double-blind Phase IIa trial reported significant healing benefits at 0.5 and 1.6 mg/mL, but not 3.2 mg/mL, where increased local inflammation was observed. A Phase IIb was reportedly initiated; results have not been published, limiting confidence in durability and generalizability.
• Melanoma (intratumoral LL-37): A Phase 1/2 microtrial at MD Anderson enrolled 4 participants (completed). Public reporting is sparse; efficacy and detailed safety signals remain unclear due to very small N and limited dissemination.
• COVID-19 (oral LL-37 via engineered probiotic): An open-label, single-arm preprint in 11 patients suggested tolerability and exploratory symptom improvements with transient serum LL-37 increases, but lacked controls and statistical power, precluding efficacy inference.

Host-directed induction of LL-37 (adjunctive or surrogate endpoints)

• Tuberculosis: Phenylbutyrate ± vitamin D3 upregulated LL-37 in macrophages in a dose-finding study; a subsequent randomized trial reported improved culture conversion with adjunctive therapy versus placebo, supporting biologic plausibility for host-directed therapy, though broader clinical outcomes and replication remain limited.
• Respiratory tract: A randomized trial showed vitamin D3 increased antimicrobial activity of airway surface liquid; neutralization experiments implicated LL-37 activity; however, clinical infection outcomes were not primary endpoints and real-world benefits are uncertain.
• Ulcerative colitis: A randomized trial found vitamin D increased hCAP18/LL-37 gene expression with reductions in ESR and hs-CRP, indicating immunomodulatory effects; hard clinical outcomes were not central endpoints.

Preclinical evidence (selected highlights)

• Antiviral activity: LL-37 shows in vitro and small-animal antiviral activity against RSV and other viruses, with multiple immunomodulatory mechanisms proposed.
• Oncology: Context-dependent effects; LL-37 can induce apoptosis and suppress colon tumorigenesis in preclinical models, but other literature documents pro-tumor activities in some cancers, underscoring pleiotropy and safety concerns for systemic or intratumoral use.

Key limitations, evidence gaps, and criticisms

• Sparse late-phase clinical trials: Beyond small Phase IIa/single-center studies in wounds, there is no robust Phase IIb/III dataset directly administering LL-37; unpublished follow-ons limit confidence.

• Small samples and short follow-up: DFU and venous leg ulcer trials had modest Ns and short durations, hindering assessment of durability, recurrence, and rare adverse events.

• Dose-dependent inflammation/toxicity: High topical doses increased local inflammation in venous ulcers, signaling a narrow therapeutic window and immunostimulatory risks.

• Delivery and stability challenges: LL-37 is susceptible to proteolysis and loss of activity in physiological milieus; topical stability and skin proteases may limit efficacy; formulation/nanocarrier strategies are early-stage.

• Translational disconnects: Many potent in vitro antimicrobial effects are diminished by salts/serum; host immunomodulation is complex and context-specific, complicating dose selection and endpoint choice; vitamin D–induction results are biologically supportive but do not equate to clinical efficacy of exogenous LL-37.

• Safety/pleiotropy concerns: LL-37 can drive mast cell IL-31 and other pruritogenic mediators, suggesting potential to exacerbate inflammatory skin symptoms; context-dependent oncologic activities raise caution for systemic/intratumoral use.

• Resistance and host-environment effects: Early beliefs that AMPs avoid resistance are questioned; bacteria may develop tolerance/adaptation; biofilm contexts and host factors limit activity; these issues reduce generalizability of in vitro potency data.

• Quality: Moderate for topical wound care signals (Phase IIa-quality evidence with small, controlled trials); low for oncology and COVID-19 (very small or uncontrolled studies). Induction strategies provide supportive biology but limited clinical endpoints.

• Extent: Broad preclinical and mechanistic base; narrow clinical program with few small RCTs and limited late-phase progression. Evidence is most supportive in chronic wound healing, but still preliminary for regulatory-grade claims.

• Priority gaps: Larger, multi-center Phase IIb/III trials in wound indications; rigorous pharmacokinetics/pharmacodynamics and dose–response to avoid inflammatory toxicity; long-term safety; standardized, clinically meaningful endpoints; delivery/stability innovations validated in humans; head-to-head comparisons with standard of care; robust oncology trials with careful patient selection given pleiotropy.

Embedded clinical-study summary

Evidence Gaps and Limitations#

The current evidence base for LL-37 consists primarily of preclinical studies. Key limitations include:

• No completed randomized controlled trials in humans
• Most data derived from animal models, limiting direct translatability
• Publication bias may favor positive results
• Long-term safety data in humans is not available
• Optimal dosing for human applications has not been established

Key Research Findings#

The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface, published in Proceedings of the National Academy of Sciences (Bals R et al., 1998; PMID: 9689116):

Demonstrated that LL-37 is produced by airway epithelial cells, secreted onto the airway surface, and displays broad antimicrobial activity that synergizes with lactoferrin and lysozyme

• LL-37 is expressed and secreted by human airway epithelial cells
• Broad-spectrum antimicrobial activity at the airway surface is salt-sensitive

Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils, published in Antimicrobial Agents and Chemotherapy (Turner J et al., 1998; PMID: 9736536):

Characterized LL-37 broad-spectrum antimicrobial activity, membrane permeabilization, LPS binding with high affinity, and alpha-helical conformation in lipid environments

• LL-37 exhibits broad-spectrum activity against bacteria and fungi
• Binds E. coli LPS with high affinity and positive cooperativity
• Adopts alpha-helical conformation in membrane-mimetic environments

An angiogenic role for the human peptide antibiotic LL-37/hCAP-18, published in Journal of Clinical Investigation (Koczulla R et al., 2003; PMID: 12782669):

Demonstrated that LL-37 activates endothelial cells via FPRL1 and promotes angiogenesis and arteriogenesis in multiple in vivo models

• LL-37 promotes angiogenesis and arteriogenesis via FPR2/FPRL1
• CRAMP-deficient mice show decreased wound vascularization

LL-37 protects rats against lethal sepsis caused by gram-negative bacteria, published in Antimicrobial Agents and Chemotherapy (Cirioni O et al., 2006; PMID: 16641434):

LL-37 at 1 mg/kg IV reduced lethality and bacterial burden in rat sepsis models, with effects comparable to polymyxin B

• LL-37 significantly reduced lethality in rat gram-negative sepsis models
• Multi-log CFU reductions in blood, peritoneum, and organs
• Neutralized endotoxin and lowered TNF-alpha

Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages, published in BMC Pulmonary Medicine (Mily A et al., 2013; PMID: 23590701):

PB 500 mg b.i.d. plus vitamin D3 5000 IU daily increased LL-37 transcript and peptide in macrophages and enhanced intracellular M. tuberculosis killing

• Phenylbutyrate plus vitamin D3 upregulated LL-37 in human macrophages
• Enhanced intracellular M. tuberculosis killing

Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers, published in Wound Repair and Regeneration (Mahlapuu M et al., 2021; PMID: 34687253):

Phase IIb RCT of topical LL-37 in 149 patients with hard-to-heal venous leg ulcers showed no overall benefit but significant improvement in the large-ulcer subgroup at 0.5 mg/mL

• No significant improvement in the full study population
• Prespecified subgroup with ulcers >=10 cm2: complete closure 28.1% vs 8.1% placebo (P=0.0458)

Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer, published in Archives of Dermatological Research (Miranda E et al., 2023; PMID: 37480520):

RCT of topical LL-37 cream in diabetic foot ulcers showed significantly greater granulation index increases versus placebo at multiple time points

• LL-37 cream increased granulation index at days 7, 14, 21, and 28 versus placebo
• IL-1alpha, TNF-alpha, and aerobic colonization were not significantly reduced

Related Reading#

• LL-37 research studies and evidence
• LL-37 dosing protocols
• LL-37 side effects profile
• KPV research guide
• TB500 research guide