LL-37

1. 01Immune system

   The body makes it as an inactive precursor

   Your white blood cells and skin cells make a longer, inactive form of the protein and store it. A vitamin D signal can turn up how much is made. Cutting the longer protein at the right spot frees the active piece, LL-37.

   For experts

   LL-37 is the C-terminal 37 residues of the 170-residue precursor hCAP-18 (CAMP gene; residues 134-170). hCAP-18 is stored in neutrophil granules and, after exocytosis, proteinase 3 alone among the azurophil-granule serine proteases cleaved it to LL-37 in the study of Sørensen et al. The CAMP promoter contains a vitamin D response element bound by the vitamin D receptor, so 1,25-dihydroxyvitamin D3 induced CAMP in human myeloid, keratinocyte and colon-cancer cell lines and in primary human bone-marrow macrophages, and Toll-like receptor activation of human macrophages raised cathelicidin through the vitamin D pathway. These are human-cell laboratory findings. The response element is present in primates but not in mouse, rat or dog genomes, so rodents are an imperfect model.[src][src][src]

2. 02Skin

   Skin injury switches it on

   When skin is cut, the skin and nearby white blood cells make a lot more of this protein for a couple of days. Long-lasting ulcers seem to be low in it at the wound edge, which is one reason it was tried as a treatment.

   For experts

   In human skin wounds, hCAP18 rose after injury, peaked at about 48 hours, and fell back to baseline on wound closure; it was found in the inflammatory infiltrate and the migrating epithelium. In chronic ulcers, levels were low and immunoreactivity was absent in ulcer-edge epithelium. In an ex vivo organ-cultured human skin wound model, affinity-purified anti-LL-37 antibodies reduced re-epithelialisation in a concentration-dependent way, and Ki67 staining was lost in inhibited wounds, suggesting a role in epithelial proliferation. This is correlational and ex vivo evidence; it does not by itself show that supplying LL-37 heals ulcers.[src]

3. 03Immune system

   It punches through germ membranes

   LL-37 is positively charged and germ surfaces are negatively charged, so it sticks to them. It bends into a spiral shape and damages the germ's outer skin. At high levels in a dish it can also hurt human cells, but adding human blood serum blocked that in the tests.

   For experts

   LL-37 is cationic and amphipathic. In water it is disordered; anions and increasing peptide concentration drove a cooperative transition to an alpha-helix consistent with oligomer formation, and helicity correlated with antibacterial activity. The NMR structure in micelles shows a curved helix-bend-helix spanning residues 2-31 with a disordered C-terminal tail, and aromatic and arginine side chains contacting anionic lipid micelles. The minimal inhibitory concentration against E. coli was 5 micromolar, while cytotoxicity against several eukaryotic cell types appeared at 13-25 micromolar; human serum inhibited both antibacterial and cytotoxic activity. These are in vitro results.[src][src]

4. 04Immune system

   It calls in other immune cells

   LL-37 also works like a flare. It attracts white blood cells to the spot and can set off a signal that makes them release an alarm chemical called interleukin-1 beta. These effects were shown in human cells in the lab.

   For experts

   LL-37 was chemotactic for human monocytes, neutrophils and T cells and induced Ca2+ mobilisation in FPRL1-transfected HEK293 cells and in monocytes, with cross-desensitisation by an FPRL1-specific agonist, indicating FPRL1 (FPR2) as a receptor. In LPS-primed human monocytes, LL-37 triggered ATP release, membrane permeability, caspase-1 activation and IL-1 beta release via P2X7, without cytotoxicity in that system. Both findings come from cell experiments; in vivo relevance in humans is inferred rather than proven.[src][src]

5. 05Skin

   It nudges lining cells to grow and signal

   LL-37 can also talk to the cells that line the skin and airways. In lab dishes it switches on their growth and alarm signals. This may be part of how it helps wounds close, but that link has not been proven in people.

   For experts

   In human airway epithelial cells, LL-37 activated MAPK/ERK and IL-8 release through metalloproteinase-mediated shedding of membrane-anchored EGFR ligands and consequent EGFR transactivation, with blocking by EGFR kinase, MEK and metalloproteinase inhibitors. This was shown in airway cells, not skin; the skin-wound data in the previous step point to a proliferative role but do not identify the receptor.[src][src]

6. 06Immune system

   Too much can drive inflammation

   In psoriasis and rosacea, skin has too much LL-37 or unusual cut-up forms of it. It can bind the body's own DNA and trick immune cells into thinking there is a virus, which fuels swelling and redness. So more LL-37 is not always better.

   For experts

   In psoriatic skin, LL-37 bound self-DNA into aggregated, condensed complexes retained in early endosomes of human plasmacytoid dendritic cells, triggering TLR9 and type I interferon production, proposed as a driver of autoimmunity in psoriasis. In rosacea, patients' facial skin had abnormally high cathelicidin and different proteolytic fragments, associated with raised stratum corneum tryptic enzyme; in mice, injecting rosacea-type fragments or adding the enzyme increased skin inflammation, and Camp-deficient mice lacked the enzyme-driven inflammation. Human data here are observational or ex vivo; the causal experiments were in mice.[src][src]

7. 07Skin

   Applied to leg ulcers, early results looked promising

   In one small trial, people with stubborn leg ulcers who got the lower two strengths of LL-37 on the wound healed faster than those on placebo. The highest strength did not help. The trial was small and short, so it needs repeating.

   For experts

   In the first-in-man randomised, double-blind, placebo-controlled trial (34 participants with hard-to-heal venous leg ulcers, twice-weekly topical applications for 4 weeks after a 3-week placebo run-in), healing rate constants for the two lower strengths were about six- and three-fold higher than placebo (p = 0.003 and p = 0.088); mean ulcer area fell 68% and 50% in those groups; the highest strength did not differ from placebo; no local or systemic safety concerns were reported. The authors called for further investigation. I did not find a published larger follow-up trial in the sources I checked.[src]

8. 08Skin

   Injected into melanoma tumours in a tiny study

   Researchers also injected LL-37 into melanoma skin tumours in a very small study of four people, hoping to wake up the immune system against the cancer. That study cannot show whether it works. One person developed unusual skin growths that cleared after treatment stopped.

   For experts

   NCT02225366 was a single-arm phase 1/2 dose-finding study of weekly intratumoral LL-37 injections into cutaneous or subcutaneous melanoma lesions, motivated by preclinical evidence of plasmacytoid dendritic cell activation. It enrolled 4 people; the posted results cover 3. A published case report from this programme described a patient with stage IIIC melanoma who had shrinkage of injected lesions but developed multiple verrucous papules and a vesiculo-bullous lesion with lichenoid infiltrate and keratoacanthoma-like epithelial atypia about 45 days after starting, which resolved within 2 months of stopping. Separately, a 2023 study found LL-37 staining rose with melanoma T stage and that LL-37 stimulated pro-angiogenic and matrix-degrading factors in melanoma cells and macrophages in vitro, raising the possibility of tumour promotion. Evidence on tumour effects is conflicting and minimal.[src][src][src]

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