the antimicrobial peptide your own skin makes
1995
Your skin manufactures its own antibiotic — two leucines opening a 37-residue chain, which is literally what "LL-37" means — and in psoriasis your immune system turns that very molecule into a weapon against you.
The trail begins in 1989, not with LL-37 but with its oddly-named parent molecule. Researchers picking apart pig neutrophils found a small protein that blocked an enzyme called cathepsin L, so they named it, with zero flair, cathelin — short for "cathepsin L inhibitor." Only later did anyone realize this cathelin piece was really a molecular shipping label: a conserved tag bolted onto a whole family of otherwise unrelated germ-killing peptides waiting to be cut loose. In 1995, Margherita Zanetti, Renato Gennaro and Domenico Romeo at the University of Trieste spotted the pattern across species and christened the family cathelicidins.
That same year the human member turned up, courtesy of the wider Stockholm antimicrobial-peptide research network that traced back to Hans Boman's pioneering work on insect and pig antibiotics. At the Karolinska Institute, Birgitta Agerberth fished a novel 39-residue peptide out of a bone-marrow gene library and named it FALL-39, after its first four amino acids. A companion paper in 1996 (Gudmundsson et al.) then delivered a twist: the actual mature peptide snipped out of the precursor protein hCAP-18 wasn't the predicted 39-residue chain, but a slightly shorter fragment — 37 residues, trimmed by two off the front, now starting with two leucines instead of the predicted Phe-Ala-Leu-Leu. It was renamed LL-37 for that corrected structure: not a lab-code mystery, but a literal description of the real, re-sequenced peptide.
Then came a discovery that solved a century-old medical mystery. Before antibiotics, doctors shipped tuberculosis patients to mountain sanatoria for sunshine and cod-liver oil — the "sunshine cure" championed by Niels Finsen and Auguste Rollier, which empirically worked but was written off as folk medicine once antibiotics arrived. In 2006, Philip Liu, Robert Modlin and colleagues showed in Science that when immune cells detect TB, they convert vitamin D into its active form, which flips on the very same gene found in 1995 and floods the cells with LL-37 to kill the bacteria directly. Sunlight, it turned out, had been the hidden active ingredient of those hillside sanatoria all along.
There's a sting in the tale. In 2007, Michel Gilliet's group (Lande et al., in Nature) showed LL-37 doesn't only kill microbes — it can also grab fragments of your own DNA spilled from dying skin cells, bundle them into dense complexes, and fool immune sentinels into reacting as if they've spotted a virus, triggering a runaway interferon response. The exact peptide built to guard the skin barrier becomes, in the wrong context, a root driver of psoriasis: your own defender turned against you.
The discovery timeline here is accurate and well-corroborated, but one popular shortcut is wrong: LL-37 is not simply FALL-39 given a snappier name. The originally predicted 39-residue FALL-39 and the actual mature 37-residue LL-37 are genuinely different sequences — LL-37 is two amino acids shorter off the front — so the story reflects that real re-sequencing rather than a tidy relabel.
LL-37 is not approved as a drug anywhere and holds no FDA approval for any indication; today it lives mostly as a laboratory research reagent and, more dubiously, as a compounded gray-market "research peptide" sold online despite that status. Its strongest human data is topical: a 2021 phase IIb trial in diabetic and venous leg-ulcer patients hinted at faster closure in larger wounds (28.1% vs 8.1% on placebo) but didn't clearly hit its primary endpoint, while a 2023 trial of LL-37 cream for diabetic foot ulcers reported improved healing. It remains a hot lead against drug-resistant pathogens like MRSA and biofilms — bacteria have had far less evolutionary time to adapt to it than to conventional antibiotics — but its double life as both germ-killer and autoimmune trigger (implicated in psoriasis and lupus) makes it far harder to tame than its "natural antibiotic" reputation suggests.
