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ll-37

Properties1
aliasesLL-37, cathelicidin LL-37, hCAP-18 C-terminal peptide, antimicrobial peptide LL-37, CAMP C-terminal peptide

15 min read

LL-37 (Cathelicidin)

LL-37 is the sole human cathelicidin — a 37-amino-acid cationic amphipathic antimicrobial peptide derived from proteolytic cleavage of the hCAP-18 precursor encoded by the CAMP gene. It is expressed in neutrophils, monocytes, NK cells, mast cells, and epithelial cells of the skin, airway, and gut. LL-37 disrupts bacterial membranes, neutralizes bacterial lipopolysaccharide (LPS), and modulates innate immune signalling via the formyl-peptide receptor 2 (FPR2). Therapeutic application of the native peptide has been hampered by rapid enzymatic degradation, short plasma half-life, and dose-dependent host-cell toxicity at concentrations above the bactericidal minimum inhibitory concentration. LL-37’s aging relevance rests on its role as a declining innate immune effector — vitamin D-regulated CAMP expression falls with aging, contributing to impaired antimicrobial defence in aged skin, airway, and gut.

Parent protein / gene biology: See camp for the full CAMP gene / hCAP-18 precursor biology, including gene structure, tissue expression atlas, and storage in neutrophil secondary granules.

Identity

FieldValue
PubChem CID16198951
Molecular formulaC205H340N60O53
Molecular weight~4,493 Da (~4.5 kDa)
Length37 amino acids
SequenceLLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES
ClassCathelicidin family; cationic amphipathic peptide
Charge (physiological)+6 (net positive; drives electrostatic targeting of anionic bacterial membranes)
WHO-INNNone assigned for native LL-37; derivatives under separate development programs
ChEMBLNot assigned (biologic peptide; ChEMBL tracks small-molecule bioactivity) needs-canonical-id

Human-specificity: LL-37 is the only cathelicidin in humans and non-human primates. Rodents express the ortholog CRAMP (cathelin-related antimicrobial peptide, encoded by Camp); cattle express multiple bovine cathelicidins (BMAP-28, indolicidin, others). The VDRE (vitamin D response element) driving CAMP expression is present in primate genomes but absent from mouse, rat, and dog 1, explaining why mouse models cannot directly proxy human CAMP/VD regulation.

Biosynthesis and processing

hCAP-18 (18 kDa) is synthesised as a prepropeptide and stored in the secondary (specific) granules of neutrophils. Upon neutrophil degranulation and secretion, the 133-residue proprotein is cleaved extracellularly by proteinase 3 (PR3, a serine protease in the azurophil granule exocytate) to release the 37-residue C-terminal LL-37 fragment 2. The cleavage is extracellular rather than intraphagosomal — the active peptide is generated in the pericellular space rather than inside the phagosome. Seminal plasma contains an alternative processing pathway in which gastricsin cleaves hCAP-18 to the 38-residue ALL-38, an equipotent antimicrobial peptide active at vaginal pH 3.

Full biology of the CAMP gene, tissue expression, and hCAP-18 protein structure: see camp.

Mechanism of action

1. Membrane permeabilization (antimicrobial)

LL-37 is cationic (+6) and amphipathic, adopting an alpha-helical conformation in lipid environments. It targets the anionic phospholipid headgroups of bacterial membranes (phosphatidylglycerol, cardiolipin) while mammalian membranes (predominantly zwitterionic phosphatidylcholine) are preferentially spared at bactericidal concentrations.

Mechanistic model — contested:

ModelEvidenceSource
Toroidal pore — peptide induces positive membrane curvature strain; pores form with peptide intercalated in a curved bilayerSolid-state NMR of DMPC/DMPG bilayers; surface-parallel helix orientation; positive curvature induction4
Carpet / detergent — peptide lies surface-parallel and disrupts bilayer integrity cooperatively without forming discrete pores; supported by helix-break-helix structure in DPC micellesNMR structure in DPC micelles; break at K12; argues against discrete pore5

contradictory-evidence — The two models are not mutually exclusive (lipid composition and peptide concentration may favour different outcomes). Neither has been directly visualised at atomic resolution in a native membrane. The biophysics community has not reached consensus as of 2026.

2. LPS neutralization

LL-37 directly binds the lipid-A acyl chains of gram-negative bacterial lipopolysaccharide (LPS/endotoxin), preventing LPS from engaging TLR4 on macrophages and thereby attenuating the endotoxaemia-driven inflammatory cascade 6. This mechanism is distinct from membrane killing and operates at sub-bactericidal concentrations. needs-replication — primary source for LPS neutralization by LL-37 specifically (rather than other defensins) is predominantly biochemical; in vivo neutralization at therapeutic doses is not well-characterised.

3. Immunomodulation via FPR2

LL-37 acts as an agonist at FPR2 (formyl-peptide receptor 2; FPRL1), a GPCR expressed on neutrophils, monocytes, and macrophages. FPR2 engagement by LL-37 promotes:

  • Enhanced phagocytosis of bacteria by macrophages, including upregulation of Fc receptor expression 7
  • Chemotaxis of neutrophils and monocytes to sites of infection
  • Redirection of poly(I:C)/TLR3 signalling via FPRL1-dependent endocytic trafficking in human (but not mouse) cells 8

The FPR2 immunomodulatory axis is active at concentrations below the MIC for direct membrane killing, suggesting LL-37 has a dual dose-dependent role: immunomodulatory at low concentrations, bactericidal at higher concentrations.

Vitamin D regulation of CAMP expression

CAMP is a direct transcriptional target of the vitamin D receptor (VDR). The CAMP promoter contains a consensus vitamin D response element (VDRE) within a primate-specific SINE element; 1,25-dihydroxyvitamin D3 (calcitriol) binding to VDR upregulates CAMP expression strongly in myeloid cells (neutrophils, monocytes, macrophages) 1.

TLR–VD axis: TLR1/2 triggering in human macrophages upregulates both VDR and CYP27B1 (25-OH D→1,25-OH D hydroxylase), locally generating calcitriol, which then induces CAMP → LL-37 → intracellular killing of Mycobacterium tuberculosis 9. This paracrine VD-cathelicidin cascade connects innate pattern recognition directly to antimicrobial effector production.

Aging implication: Vitamin D synthesis in skin declines with age (reduced 7-dehydrocholesterol, decreased sun exposure, impaired renal 1α-hydroxylation). Low 25-OHD is associated with reduced cathelicidin production in macrophages. The TLR–VD axis provides a mechanistic pathway linking age-related VD insufficiency to impaired innate antimicrobial defence. needs-replication — direct demonstration that VD supplementation in older adults restores LL-37 levels to young-adult range is limited to small studies.

Aging relevance

Dermal adipose tissue (dermal fat) is a major source of cathelicidin in skin. In neonatal skin, THY1hi PDGFRA+ dermal fibroblast (dFB) progenitors express high cathelicidin during adipogenic differentiation and mount robust antimicrobial responses to Staphylococcus aureus. This capacity is lost progressively postnatally and further declines with aging via TGF-β1-mediated suppression of the adipogenic differentiation program in this dFB progenitor population (the suppression operates on the differentiation pathway, not on direct fibroblast cathelicidin transcription). TGF-β receptor blockade partially restores antimicrobial fibroblast function and enhances 1-year-old C57BL/6 male mouse resistance to S. aureus infection 10.

DimensionStatus
Pathway conserved in humans?Yes (CAMP/LL-37 is human-specific; TGF-β signalling is conserved)
Phenotype (AMP decline) conserved in humans?Partial — human skin aging shows reduced AMP expression; direct LL-37 quantitation across decades is limited
Replicated in humans?No — TGF-β blockade to restore LL-37 is preclinical only

needs-human-replication — Age-stratified quantitation of LL-37 in human skin, airway, and blood across the full adult lifespan with standardised methods is not well-characterised.

Hallmark connection

LL-37 connects to disabled-adaptive-immunity as an innate immune effector whose decline with aging impairs antimicrobial defence. Secondary connection to dysbiosis — AMP decline at mucosal surfaces alters the balance of mucosal microbiota, with potential downstream effects on gut and airway microbial composition.

Therapeutic applications and clinical development

The native LL-37 peptide has been evaluated therapeutically primarily in chronic wound healing and local infection contexts, not systemic aging indications.

Venous leg ulcer (Phase 2 RCT)

The first-in-human trial of LL-37 (Grönberg et al. 2014, n=34; randomised placebo-controlled) found dose-dependent efficacy in hard-to-heal venous leg ulcers over 4 weeks of twice-weekly application. Topical LL-37 at 0.5 mg/mL produced a healing-rate constant ~6-fold higher than placebo; 1.6 mg/mL produced ~3-fold higher healing rate 11. No safety concerns were reported at these topical doses, consistent with the expectation that topical concentrations do not reach systemic host-cell-toxic levels. This remains the strongest human-controlled evidence for LL-37 as a therapeutic peptide. Caveat: n=34 and full methods details are not independently verified against the primary PDF (closed-access, not_oa); n and doses are consistent with how Miranda 2023 (ref 21 therein) characterises this trial. no-fulltext-access

Diabetic foot ulcer (Phase 2 RCT)

Miranda et al. 2023 (n=25; 13 LL-37, 12 placebo; randomised double-blind controlled; NCT04098562; conducted January 2020–June 2021 in Jakarta) evaluated topical LL-37 cream (0.025 mL/cm², 0.5 mg/g) in mild-to-moderate diabetic foot ulcers. Granulation index was significantly greater in the LL-37 group on all four assessment days (day 7: p=0.031; day 14: p=0.009; day 21: p=0.006; day 28: p=0.037). No significant reduction in inflammatory markers (IL-1α, TNF-α) or aerobic bacterial colonisation counts was observed (all p>0.05) 12. The wound healing signal is consistent with the earlier venous leg ulcer data; the lack of anti-inflammatory and anti-colonisation effects suggests the wound-healing benefit may operate through non-antimicrobial pathways (angiogenesis, keratinocyte migration) at therapeutic topical doses. Note: both IL-1α and TNF-α increased in both groups, consistent with active wound proliferation phase; bacterial resistance to LL-37 (S. aureus, Pseudomonas sp.) is the authors’ favoured explanation for the lack of antimicrobial effect.

Derivatives and analogues in development

The native LL-37 peptide faces major pharmacological limitations (see Limitations below). Several clinical-stage programmes use LL-37 derivatives rather than the native sequence:

AgentRelationship to LL-37StageIndication
Omiganan (MBI 226)Indolicidin-derived cationic AMP; structural analogue classPhase 3 (historical; multiple indications)Catheter-site infections, rosacea; native LL-37 is structurally distinct
OP-145LL-37 fragment (residues 9–24); designed for Pseudomonas-biofilm disruptionPhase 1/2 (ear infection)Chronic suppurative otitis media
P60.4AcLL-37 truncation/analoguePhase 1/2Wound infection
Novexatin / NP213Arginine-based AMP; same therapeutic class but distinct sequencePhase 2Onychomycosis

Note: No active ClinicalTrials.gov studies are recruiting specifically for native LL-37 in aging-relevant indications (0 RECRUITING/ACTIVE_NOT_RECRUITING as of 2026-05-09). Active wound-healing trials use derivatives or combination agents.

FDA 503A context

The native LL-37 peptide appears on the FDA 503A PCAC bulks-list review as a compounded peptide. This regulatory context (R36 batch) positions LL-37 as a compounded therapeutic ingredient under review for safety and efficacy sufficiency for compounding. The PCAC review does not constitute FDA approval; the compound remains investigational for systemic aging-related indications.

Pharmacology and limitations

Enzymatic instability

LL-37 is rapidly degraded by proteases present at sites of infection and in biological fluids. Serine proteases (including the same proteinase 3 that generates LL-37 from hCAP-18 in the correct context), metalloproteinases, and thrombin all cleave LL-37 fragments at wound sites. This limits bioavailability of systemically administered native peptide and is a primary driver of development focus on more stable analogues. long-term-unknown — plasma half-life of exogenous LL-37 in humans has not been well-characterised in published clinical PK studies.

Host-cell toxicity at higher concentrations

At concentrations substantially above the minimum inhibitory concentration (typically ≥10 µM depending on cell type and membrane composition), LL-37 begins to disrupt mammalian cell membranes. This dose-dependent host-cell toxicity limits the therapeutic window for systemic delivery and is a class-level property of cationic AMPs. Topical application to wound beds, where concentrations can be controlled locally, has a more favourable safety profile than systemic administration.

Selectivity index

The selectivity index (MIC_bacteria / MHC_mammalian cells) for native LL-37 is moderate (~10–50 depending on cell type and assay conditions). This is sufficient for topical antimicrobial use but insufficient for systemic dosing at concentrations needed to clear biofilm or systemic infection. Most development programmes for LL-37-derived peptides have focused on improving this selectivity index.

Immunostimulatory concerns

LL-37 is a potent activator of plasmacytoid dendritic cells (pDCs) — it promotes TLR9-dependent IFN-α production by forming complexes with self-DNA, a mechanism implicated in the pathogenesis of lupus and psoriasis. Elevated LL-37 in psoriatic skin is a known disease driver. Therapeutic elevation of LL-37 at systemic levels carries a theoretical risk of exacerbating autoimmune conditions in susceptible individuals.

Knowledge gaps and limitations

  • Systemic delivery unresolved: No published Phase 1 trial of systemically administered native LL-37 in humans. dose-response-unclear
  • Mechanism model contested: Toroidal pore vs carpet model for membrane disruption has not been resolved by direct experimental evidence at physiological conditions 4 5. contradictory-evidence
  • Aging-specific evidence thin: Direct demonstration that LL-37 decline drives infection susceptibility in older humans, or that therapeutic LL-37 restoration improves aging-relevant endpoints, is preclinical only 10. needs-human-replication
  • LPS neutralization in vivo unconfirmed: The endotoxaemia-protective role of LL-37 is mechanistically plausible but demonstrated primarily in vitro. needs-replication
  • Vitamin D–LL-37–aging axis: Whether VD supplementation in older adults measurably restores LL-37 to young-adult levels in skin and airway is not established by large well-controlled trials. needs-human-replication
  • ChEMBL ID absent: Native peptide biologics frequently lack ChEMBL bioactivity entries; inhibition data is assay-level, not currently in ChEMBL. needs-canonical-id
  • No DrugAge lifespan entry: LL-37 does not appear in DrugAge as of 2026-05-09.

Footnotes

Footnotes

  1. doi:10.1096/fj.04-3284com · Gombart AF, Borregaard N, Koeffler HP · FASEB J 2005;19(9):1067–1077 · in-vitro (promoter reporter + myeloid cell VDR-binding assay) · identifies functional VDRE in CAMP promoter conserved across primates but absent in mouse/rat/dog; 1,25-OH-D3 strongly upregulates CAMP in myeloid cells; defines the vitamin D → cathelicidin regulatory axis · locally available: not_oa ↩ ↩2

  2. doi:10.1182/blood.v97.12.3951 · Sørensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, Borregaard N · Blood 2001;97(12):3951–3959 · in-vitro + ex-vivo (neutrophil degranulation) · model: human neutrophil secondary granule exocytate · demonstrates proteinase 3 is the extracellular enzyme solely responsible for hCAP-18 → LL-37 cleavage after exocytosis; cleavage is extracellular, not intraphagosomal (hCAP-18 enters phagolysosome but is not cleaved there); elastase and cathepsin G can cleave hCAP-18 in vitro but are excluded by inhibitor/immunoprecipitation experiments from acting on hCAP-18 in exocytosed material; N-terminal sequencing confirmed LL-37 sequence (L)LGDFFRKSK from proteinase 3 cleavage product · locally available: completed ↩

  3. doi:10.1074/jbc.M301608200 · Sørensen OE, Gram L, Johnsen AH, Andersson E, Bangsbøll S, Tjabringa GS, Hiemstra PS, Malm J, Egesten A, Borregaard N · J Biol Chem 2003;278(31):28540–28546 · in-vitro + ex-vivo (postcoital vaginal samples) · model: seminal plasma hCAP-18 cleavage by gastricsin (pepsin C, an aspartic protease) at vaginal pH (pH 4) generating 38-residue ALL-38 (N-terminus ALLGDFFRKS confirmed by sequencing); cleavage abolished by pepstatin A and pepsinostreptin; gastricsin immunoprecipitation abolishes cleavage; antimicrobial activity of ALL-38 equal to LL-37 against E. coli, S. aureus, B. megaterium; in-vivo processing confirmed in postcoital vaginal samples; documents alternative processing pathway; not the canonical neutrophil pathway · locally available: completed (OA via CC BY) ↩

  4. doi:10.1021/bi034520a · Henzler-Wildman KA, Lee DK, Ramamoorthy A · Biochemistry 2003;42(21):6545–6558 · in-vitro (solid-state NMR of bilayer lipid systems) · demonstrates surface-parallel LL-37 helix orientation; positive curvature strain consistent with toroidal-pore mechanism; rules out barrel-stave pore and detergent-like micelle formation · n/a (biophysics assay) · locally available: not_oa ↩ ↩2

  5. doi:10.1021/bi702036s · Porcelli F, Verardi R, Shi L, Henzler-Wildman KA, Ramamoorthy A, Veglia G · Biochemistry 2008;47(20):5565–5572 · in-vitro (solution NMR in DPC micelles) · helix-break-helix conformation with break at K12; hydrophobic face buried in micelle; argues for non-pore carpet-like mechanism; contradicts strict toroidal-pore model · locally available: not_oa ↩ ↩2

  6. doi:10.1097/00062752-200201000-00004 · Lehrer RI, Ganz T · Curr Opin Hematol 2002;9(1):18–22 · review · contextualises cathelicidin storage in secondary granules and LL-37 liberation by proteinase 3; discusses LPS-neutralization role of cationic AMPs including LL-37 · locally available: not_oa ↩

  7. doi:10.1189/jlb.3HI0313-168R · Wan M, van der Does AM, Tang X, Lindbom L, Agerberth B, Haeggström JZ · J Leukoc Biol 2014;95(6):971–981 · in-vitro (human macrophage) · LL-37 enhances phagocytosis dose- and time-dependently; upregulates Fc receptor expression; FPR2/ALX mediates phagocytic enhancement; TLR4 contributes · n/a (cell culture) · locally available: not_oa ↩

  8. doi:10.1074/jbc.M112.440883 · Singh D, Qi R, Jordan JL, San Mateo L, Kao CC · J Biol Chem 2013;288(12):8258–8268 · in-vitro · LL-37 (but not mouse mCRAMP) stimulates TLR3 signalling via FPRL1-dependent clathrin-independent endocytic pathway; binds dsRNA; LL-37 + poly(I:C) complex traffics to Rab5 endosomes; effect is human-specific · model: human (BEAS-2B lung epithelial) and mouse cell lines · locally available: not_oa · NOTE: DOI corrected from erroneous 10.1074/jbc.M112.442350 (that DOI resolves to an unrelated cyanophage RNAP paper); correct DOI confirmed via PMID 23386607 ↩

  9. doi:10.1126/science.1123933 · Liu PT, Stenger S, Li H, Wenzel L, Tan BH, et al. · Science 2006;311(5768):1770–1773 · in-vitro (human macrophage) + observational (serum 25-OHD) · TLR1/2 triggering upregulates VDR + CYP27B1 → local 1,25-OH-D synthesis → CAMP induction → killing of intracellular Mtb; serum 25-OHD associates with cathelicidin mRNA induction capacity · model: human macrophages; African-American individuals with low 25-OHD showed impaired cathelicidin response · locally available: not_oa ↩

  10. doi:10.1016/j.immuni.2018.11.003 · Zhang LJ, Chen SX, Guerrero-Juarez CF, Li F, Tong Y, Liang Y, Liggins M, Chen X, Chen H, Li M, Hata T, Zheng Y, Plikus MV, Gallo RL · Immunity 2019;50(1):121–136.e5 · in-vivo (mouse) · neonatal skin adipogenic fibroblasts are high-cathelicidin source; TGF-β suppresses this adipogenic dFB population postnatally and with aging; TGF-β receptor blockade restores antimicrobial function in adult mice and enhances S. aureus resistance · model: C57BL/6 mice (neonatal vs adult) · locally available: pending (green OA via PMC7191997; download failed — retry if needed) · PMID: 30594464 ↩ ↩2

  11. doi:10.1111/wrr.12211 · Grönberg A, Mahlapuu M, Ståhle M, Whately-Smith C, Rollman O · Wound Repair Regen 2014;22(5):613–621 · rct · n=34 (from Miranda 2023 ref 21; not independently verified against primary PDF); first-in-human RCT of topical LL-37 in chronic venous leg ulcers; 4 weeks twice-weekly application; dose-dependent healing: 0.5 mg/mL ~6× higher healing rate constant vs placebo; 1.6 mg/mL ~3× higher; no adverse effects · locally available: not_oa no-fulltext-access ↩

  12. doi:10.1007/s00403-023-02657-8 · Miranda E, Bramono K, Yunir E, Reksodiputro M, Suwarsa O, Rengganis I, Harahap AR, Subekti D, Suwarto S, Hayun H, Bardosono S, Baskoro JC · Arch Dermatol Res 2023;315:2623–2633 · rct · n=25 total (13 LL-37, 12 placebo); NCT04098562; conducted January 2020–June 2021; dose 0.025 mL/cm², cream concentration 0.5 mg/g; topical LL-37 cream in diabetic foot ulcers with mild infection; granulation index significantly greater in LL-37 group on all days (day 7: p=0.031; day 14: p=0.009; day 21: p=0.006; day 28: p=0.037); no significant reduction in IL-1α or TNF-α (p>0.05 all timepoints); no significant reduction in aerobic bacterial colony counts (p>0.05); one mild irritant contact dermatitis AE in LL-37 group · locally available: completed ↩

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