LL-37 — Peptide Protocol Wiki reference

Modulates innate and adaptive immune responses.

What are the side effects of LL-37?

Comprehensive human safety data may be limited.

Is LL-37 FDA approved?

Consult the detailed side effects profile for full information.

LL-37: Antimicrobial Cathelicidin Peptide Guide | Peptide Protocol Wiki Skip to main content 🧬 Peptide Protocol Wiki Peptides Side Effects New Learn Directory Tools Blog News About ⌘K ⌘K 🌱 New to Peptides?

Start the 7-step beginner guide Peptides Side Effects New Directory Learn Tools Blog News About LL-37 📋 Overview 🧬 Molecule 🔄 Similar ⚠️ Side Effects 💉 Dosing 🔬 Research 🚨 Risks 👥 Community 📊 Community Data Home Peptides LL-37 Immune Support Healing & Tissue Repair phase2 LL-37 Also known as: Cathelicidin, CAP-18, hCAP-18, Human Cathelicidin Antimicrobial Peptide Compare with 2 peptide s Research compiled by Peptide Protocol Wiki 📅 Updated February 1, 2026 Citations Verified TL;DR LL-37 is the only human cathelicidin antimicrobial peptide, a 37-amino acid alpha-helical peptide derived from the C-terminal of hCAP-18.

Browse all immune peptides → Table of Contents 📌 TL;DR • Broad-spectrum antimicrobial activity against bacteria, fungi, and viruses • Modulates innate and adaptive immune responses • Promotes wound healing and angiogenesis in preclinical models • Neutralizes bacterial endotoxin (LPS) activity Community-Reported Side Effects Anecdotal ?

Antimicrobial immune defense, wound healing, and infection recovery support 💉 Dosing Amount 100-200 mcg daily (SC); topical per formulation Frequency Once daily, 5 days per week (SC); as directed (topical) Duration 2-4 weeks, then 2 weeks off 💊 Administration Route SC Schedule Once daily, 5 days per week (SC); as directed (topical) Timing No specific timing requirement ✓ Rotate injection sites 📅 Cycle Duration 2-4 weeks, then 2 weeks off Rest Period 2 weeks off between cycles Repeatable Yes Preparation & Storage Diluent: Bacteriostatic water ⚗️ Suggested Bloodwork ( 6 tests) CBC with differential When: Baseline Why: Baseline immune cell counts CRP When: Baseline Why: Baseline inflammation CMP with liver and kidney function When: Baseline Why: Baseline organ function Vitamin D level When: Baseline Why: Vitamin D is a key regulator of LL-37 expression CBC When: 2 weeks Why: Monitor immune response CRP When: 2-4 weeks Why: Assess inflammatory response 💡 Key Considerations → Local injection site reactions (redness, burning) are common due to immune-stimulatory properties → Contraindication: Avoid in autoimmune conditions where immune stimulation may cause flares; use cautiously in patients with mast cell disorders Subscribe to unlock this content Get weekly peptide research summaries, new study alerts, and protocol updates — free.

Restore access No thanks, continue reading Related Reading Peptide Thymosin Alpha-1 immune modulating peptide Peptide KPV anti-inflammatory tripeptide Peptide Glutathione master antioxidant tripeptide How LL-37 works at the cellular level Overview of LL-37 benefits and applications Scientific Details Molecular Formula C205H340N60O53 Molecular Weight 4493.33 Da CAS Number 154947-66-7 Sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES What is LL-37?

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).

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.

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.

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 deliver

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.

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.

ic 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.

Reported side effects of LL-37 include local injection site reactions, adjacent skin reactions.

ic 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.

Receptor/Target Cell types Upstream trigger / mechanism Key downstream signaling Functional outcomes FPR2 / ALX Neutrophils, monocytes, epithelial cells LL-37 acts as GPCR agonist or membrane-facilitated activator Gi-mediated PLC → Ca2+ flux, ERK, p38, PI3K/Akt, NADPH-oxidase → ROS, NF-κB Chemotaxis, ROS/leukotriene release, survival, angiogenesis CXCR2 Neutrophils, monocytes, endothelial cells LL-37 can functionally engage CXCR2; receptor-mediated endocytosis reported G-protein → Ca2+ mobilization, ERK, PI3K Chemotaxis, angiogenesis, receptor endocytosis/downregulation MRGPRX2 (MRGPRB2) Mast cells (skin, connective tissues) Direct agonism by LL-37 (basic peptide) → rapid activation Gαi/Gαq → Ca2+ influx, ERK, PI3K; β-arrestin patterns vary Mast cell degranulation, histamine/cytokine release; roles in rosacea/itch P2X7 Macrophages, epithelial cells, neutrophils LL-37 activates P2X7 (direct or membrane-perturbation) causing pore formation Cation flux (Ca2+/K+), pore formation → NLRP3 inflammasome, caspase‑1, IL‑1β IL‑1β release, pyroptosis modulation, autophagy, inflammasome-driven inflammation EGFR (transactivation via ADAM / HB‑EGF) Keratinocytes, airway/epithelial cells LL-37 → GPCR/ membrane effects → ADAM-mediated HB‑EGF (ectodomain she

dding) → EGFR EGFR → MAPK/ERK, PI3K/Akt signaling Proliferation, migration, wound healing, epithelial repair TLR4 (neutralization) Monocytes, macrophages, endothelium LL-37 binds/neutralizes LPS or disrupts membrane TLR4 complex formation Reduced MyD88/NF-κB activation, lower MAPK signaling Anti-inflammatory effects; reduced LPS-driven cytokines and apoptosis TLR7/8/9 (nucleic acid complexing) Plasmacytoid DCs, keratinocytes, neutrophils LL-37 forms complexes with self/viral DNA/RNA and promotes endosomal delivery Endosomal TLR → IRF pathways (type I IFN), NF-κB → cytokine induction Type I IFN production, autoimmunity (e.g., psoriasis), enhanced antiviral sensing TRPV2 / BKCa (ion channels) Epithelial, cancer cells, glia Membrane perturbation or indirect activation by LL-37 → channel opening Ca2+ influx via TRPV2, BKCa-mediated K+ efflux; downstream MAPK signaling Enhanced migration, cell motility, invasion Mac-1 (CD11b/CD18) Neutrophils, macrophages LL-37 interaction promotes integrin engagement Integrin signaling → cytoskeletal rearrangement Increased phagocytosis, adhesion, immune cell recruitment IGF1R / ErbB2 (cancer contexts) Tumor cells (various) Direct or indirect activation by LL-37 in select cancers PI3K/Akt, ERK; cross-talk with Wnt/β‑catenin reported Tumor cell proliferation, survival, metastasis promotion (context-dependent) Platelet GPVI Platelets Neutrophil-derived LL-37/CRAMP primes platelets via GPVI engagement Src / Syk → PLC → platelet activatio

n pathways Platelet activation, thrombosis and thrombo‑inflammation Intracellular GAPDH Epithelial and other cells LL-37 internalized via endocytosis (receptor- or membrane-mediated) → intracellular binding Modulation of p38 MAPK and other signaling cascades Altered inflammatory signaling, potential transcriptional/repair effects Therapeutic Applications # Therapeutic applications of LL-37 span wound healing, infectious disease immunomodulation/antiviral strategies, and early oncologic intralesional therapy.

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).

ons were common but mostly mild, infections were uncommon and non-serious, and no deaths occurred (overall serious adverse events 7.4%).