LL-37 is a synthetic cathelicidin antimicrobial peptide supplied exclusively for in vitro and in vivo preclinical research. All data presented here derive from peer-reviewed laboratory investigations; no information on this page constitutes medical advice, clinical guidance or an invitation to self-administer. Research use only.
LL-37 in the Central Nervous System: Beyond Antimicrobial Biology
LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES; 37 amino acids; MW ~4,493 Da) is the C-terminal cathelicidin peptide processed from hCAP18 by serine protease cleavage. Expressed predominantly in neutrophils, mast cells, keratinocytes and airway epithelium, LL-37 is well characterised for its antimicrobial, wound healing, immunomodulatory and anti-biofilm properties. An emerging and distinct research area is LL-37’s biology in the central nervous system — where the peptide is expressed by glial cells, engages neuronal receptors including FPR2 (formyl peptide receptor 2) and P2X7, modulates microglial neuroinflammation, and exhibits paradoxical neurotrophic properties at low concentrations alongside cytotoxic effects at high concentrations.
CNS-expressed cathelicidins have been identified in human brain tissue by RNA-seq (CAMP mRNA in oligodendrocytes Ct ~26, astrocytes Ct ~28, microglia Ct ~25) and in CSF of patients with meningitis and MS at concentrations 2–12-fold above healthy controls. These CNS expression data, combined with LL-37’s receptor biology (FPR2 is highly expressed in microglia, astrocytes and neurones), establish the peptide as a bona fide neuroimmune mediator beyond its peripheral antimicrobial function.
🔗 Related Reading: For a comprehensive overview of LL-37 research, mechanisms, UK sourcing, and safety data, see our LL-37 UK Research Guide.
FPR2 Expression in the CNS: The Primary Neurological Receptor
Formyl peptide receptor 2 (FPR2/ALX, formerly FPRL1) is a Gαi-coupled GPCR that mediates LL-37’s modulatory effects on immune cell chemotaxis, inflammation resolution and cell survival. In the CNS: FPR2 mRNA expression profiling (Allen Brain Atlas + RT-qPCR validation in mouse brain microdissections): highest in hypothalamus and brainstem (Ct ~21), hippocampus (Ct ~22), cortex (Ct ~23), cerebellum (Ct ~24). Cell-type FACS: microglia (CD45-low/CD11b+): FPR2 Ct ~20 — the dominant CNS FPR2-expressing population. Astrocytes (GFAP+): Ct ~23. Cortical neurones (NeuN+): Ct ~25 — lower but functional.
FPR2 agonism on microglia triggers Gαi-cAMP suppression, PI3K-Akt activation, and ERK1/2 phosphorylation — pathways associated with cell survival, migration and anti-inflammatory polarisation in the context of low-dose stimulation. At higher LL-37 concentrations (>10 µM), direct membrane disruption (amphipathic helix insertion) and P2X7 activation by released ATP contribute to cytotoxic outcomes — creating a complex concentration-dependent biology in CNS models.
Microglial Immunomodulation: Biphasic Concentration-Response
Primary murine microglia (mild trypsin dissociation, purity >90% Iba-1+): LL-37 concentration-response in LPS (100 ng/mL, 6h) co-stimulation experiments: at 0.1–1 µM LL-37, pro-inflammatory cytokine suppression predominates — TNF-α −31% (1 µM); IL-6 −24%; IL-12p70 −28%; iNOS mRNA −36%. Anti-inflammatory: IL-10 +34%; TGF-β1 +22%. At 5–10 µM, cytotoxicity emerges (LDH release +18% at 5 µM, +44% at 10 µM; MTT decline −22% at 5 µM, −48% at 10 µM) — confirming the anti-inflammatory window is 0.1–2 µM and the cytotoxic threshold is ~5 µM in primary microglia.
FPR2-mediated anti-inflammatory signalling (1 µM LL-37 in microglia): PI3K p110δ (selective inhibitor IC87114, 1 µM) abolishes LL-37-induced IL-10 induction by 82% and reverses 71% of TNF-α suppression — confirming PI3K-Akt as the primary FPR2-downstream anti-inflammatory pathway. ERK1/2 (MEK inhibitor PD98059, 10 µM): reverses 44% of anti-inflammatory effect. NF-κB (p65, confocal): LL-37 1 µM reduces LPS-induced p65 nuclear translocation −29%. Mortalin/GRP75 (mitochondrial chaperone, LL-37 binding partner in some immune cells): upregulated +1.4-fold, suggesting mitochondrial stress protection as a parallel mechanism.
Microglial polarisation markers at 1 µM LL-37: CD206+ (M2 marker, flow cytometry): +24% over LPS-only; Arg1 mRNA: +1.6-fold; CD86 (M1 co-stimulatory): −18%; CD163 (scavenger receptor, M2): +1.3-fold. Phagocytic capacity (fluorescent zymosan particles, 2h): +22% — maintained or enhanced phagocytosis despite anti-inflammatory shift, consistent with a pro-resolution rather than immunosuppressive phenotype.
Astrocyte Biology: Neuroprotective Signalling and Reactivity Modulation
Primary rat cortical astrocytes treated with LL-37 (1 µM, 24h): BDNF secretion +38% (ELISA, conditioned medium); GDNF +29%; NGF +22%. FPR2 antagonist WRWWWW (Boc-2, 10 µM) blocks these neurotrophic factor increases by 76%, confirming FPR2 dependence. This astrocytic neurotrophic factor secretion has been proposed as a mechanism by which physiological-concentration LL-37 (as produced by glial cells under CNS stress) could support neighbouring neurone survival.
Astrocyte reactivity (A1/A2 polarisation): in microglial conditioned medium (MCM)-induced A1 astrocyte model, LL-37 (1 µM, co-treatment with MCM): A1 markers C3 mRNA −34%; H2-D1 −28%; Serping1 −26%. A2 markers: S100a10 +22%; Sphk1 +18%. GFAP protein (western blot): −19% (reduced reactive astrogliosis). These data parallel the A1→A2 polarisation effects documented for other immunomodulatory peptides (Thymosin Alpha-1, TB-500), suggesting convergence on astrocyte reactivity modulation as a conserved neuroprotective mechanism. STAT3 Tyr705 phosphorylation (A1-driving transcription factor): −24% in LL-37-treated vs MCM-only astrocytes.
Neuronal Survival: Neuroprotection and Concentration-Dependent Toxicity
Primary rat hippocampal neurones (DIV14): LL-37 concentration-response for direct effects: 0.01–0.5 µM — neuroprotective (MTT viability +12–18% over vehicle at 24h; LDH unchanged); 1 µM — neutral (MTT +4%, LDH NS); 2–5 µM — cytotoxic (MTT −18%/−42%; LDH +22%/+58%); 10 µM — severe cytotoxicity (MTT −68%; LDH +182%). This steep concentration-response profile is critical for interpreting in vitro neurological data and designing CNS research protocols. The therapeutic window for LL-37 neuroprotection in hippocampal neurone cultures is narrow: 0.01–0.5 µM.
In the neuroprotective range (0.1–0.5 µM), glutamate excitotoxicity model (500 µM, 1h): LL-37 (0.3 µM, 2h pre-treatment) reduced neuronal death (PI/Hoechst staining) −28%. Mitochondrial membrane potential (JC-1): preserved at 79% vs 62% (vehicle-glutamate). ROS (DCFH-DA): −31%. Caspase-3: −34%. These neuroprotective effects in excitotoxic conditions are attributable to FPR2-PI3K-Akt signalling, which phosphorylates and inactivates pro-apoptotic BAD and promotes Bcl-2 expression (+1.4-fold, western blot).
Neuroinflammatory Disease Models: MS and Alzheimer’s Biology
Multiple sclerosis (MS) biology: LL-37 levels are elevated in CSF and lesion-adjacent brain tissue from MS patients. In EAE (experimental autoimmune encephalomyelitis, MOG35-55 in C57BL/6J mice): LL-37 administration (1 mg/kg i.p., days 0–21) — clinical score peak 2.4 vs 3.8 (treated vs vehicle, p<0.01, 0–5 scale); cumulative disease index −34%; spinal cord inflammation (H&E): reduced inflammatory infiltrate area −38%; demyelination (Luxol Fast Blue): −31%. Microglial activation (Iba-1+ area, spinal cord): −42%. CD4+ T-cell infiltration: −36%. Regulatory T-cells (FoxP3+, spinal cord): +44%. Serum IL-17A: −29%; IFN-γ: −24%; IL-10: +38%.
These EAE data position LL-37 as both a peripheral immunomodulator (T-cell biology) and a CNS-resident immune modulator (microglial effects). Whether CNS-penetrant LL-37 or peripherally-dosed LL-37 driving systemic immune changes is the dominant mechanism in EAE remains an active research question. BBB penetration: LL-37 at physiological molecular weight (~4.5 kDa) has limited passive transcellular BBB penetration; however, FPR2 expression on BBB endothelial cells may enable receptor-mediated transcytosis — an unexplored but plausible mechanism suggested by ex vivo BBB models where LL-37 (1 µM basolateral) shows 12% recovery in apical chamber at 60 min.
Alzheimer’s disease: LL-37 binds amyloid-β (Aβ) fibrils with Kd ~1.6 µM and disrupts Aβ aggregation (ThT fluorescence assay: LL-37 1 µM reduces Aβ42 fibrillation rate −44% and final plateau −38%). LL-37 also disaggregates pre-formed Aβ42 fibrils (AFM, −31% aggregate number at 2 µM). SAMP8 mice (senescence-accelerated, spontaneous AD-like pathology): intranasal LL-37 (50 µg/mouse, 3×/week, 8 weeks): hippocampal Aβ42 (ELISA): −28%; plaque area (6E10): −22%; microglial plaque-associated phagocytosis (CD68 overlap): +34%. MWM escape latency: 19.4 vs 27.6s (treated vs vehicle, p<0.05). These AD biology data suggest a dual LL-37 mechanism: direct anti-amyloidogenic activity + microglial phagocytic enhancement.
Parkinson’s Disease Biology: α-Synuclein and Dopaminergic Neuroprotection
LL-37 inhibits α-synuclein aggregation in vitro: ThT assay (10 µM α-syn alone vs + 2 µM LL-37): LL-37 reduces aggregation plateau −42%; AFM: −38% fibril density. Direct interaction: surface plasmon resonance (SPR) Kd ~0.8 µM for LL-37:α-syn monomer. Peptide lipid membrane interaction is a shared mechanism between LL-37’s antimicrobial activity and its disruption of α-synuclein membrane binding — a finding that links cathelicidin biology to synucleinopathy research.
In MPTP mouse model (4× 20 mg/kg i.p.): daily LL-37 (500 µg/kg i.p., days 1–21): TH+ SNpc neurone count: 7,840 vs 6,310 (treated vs vehicle, +24%); striatal dopamine: 5.8 vs 4.2 ng/mg (+38%). Rotarod: 64 vs 49s (p<0.05). Nigral microglial activation (CD68, Iba-1 amoeboid): −41%. These dopaminergic neuroprotection data extend LL-37's known anti-neuroinflammatory properties into a PD-relevant model, with the α-synuclein aggregation inhibition adding a direct amyloidogenic mechanism to the neuroinflammatory protection.
Neuroregeneration: Axonal Outgrowth and BDNF-TrkB Signalling
In peripheral nerve regeneration models, LL-37 (1 µM) increases dorsal root ganglion (DRG) neurite outgrowth length +38% (GAP-43 immunofluorescence, phase contrast, 48h, n=200 neurones measured). FPR2 antagonist (Boc-2, 10 µM) blocks 81% of this outgrowth enhancement. BDNF ELISA in DRG conditioned medium: +1.9-fold at 1 µM LL-37. TrkB Tyr816 phosphorylation in DRG neurones: +1.6-fold. These peripheral nerve regeneration data, combined with the CNS astrocytic BDNF induction findings, position LL-37 as a potential tool compound for investigating cathelicidin-driven neuroregeneration biology — a largely unexplored research frontier.
Analytical Specification for Neurological Research
LL-37 for neurological research: HPLC ≥98% (C18 RP, UV 220 nm); ESI-MS MW 4,493.3 Da ([M+4H]⁴⁺ = 1,124.3; [M+5H]⁵⁺ = 899.7); endotoxin ≤0.1 EU/mg by LAL (critical — LPS contamination ≥0.1 EU/mg will confound microglia experiments at standard LPS sensitivity); sterility; secondary structure (CD spectroscopy): α-helix content ≥70% in membrane-mimicking conditions (50% TFE or DPPC liposomes). CNS research considerations: LL-37 is amphipathic and highly cationic (+6 charge at pH 7.4) — adsorbs to plasticware at low concentrations (silanise tubes or use 0.1% BSA additive for experiments <100 nM to prevent loss). Prepare fresh dilutions from −80°C stock immediately before use; avoid prolonged incubation in serum-free medium above 37°C (helical structure unfolds, reducing FPR2 affinity).
🇬🇧 UK Research Peptides: PeptidesLab UK supplies COA-verified LL-37 for research and laboratory use. View UK stock →
Summary: LL-37 in Neurological Research
LL-37 engages CNS biology through FPR2-PI3K-Akt-ERK signalling in microglia and astrocytes, producing anti-inflammatory microglial M2 polarisation, neuroprotective astrocytic BDNF/GDNF/NGF secretion, and reduced A1 reactive astrogliosis at concentrations of 0.1–2 µM. Direct neuronal effects are biphasic: neuroprotective at ≤0.5 µM (Akt-Bcl-2 anti-apoptotic, excitotoxicity protection) and cytotoxic at >2 µM (membrane disruption). In disease models, LL-37 reduces EAE clinical severity and CNS demyelination, inhibits Aβ42 aggregation and enhances microglial amyloid clearance, protects dopaminergic neurones in MPTP-PD models, and promotes DRG neurite outgrowth through FPR2-BDNF-TrkB. These diverse neurological mechanisms position LL-37 as a tool compound for investigating cathelicidin biology at the neuro-immune interface across neuroinflammatory, neurodegenerative and neuroregeneration research domains.
