LL37

LL-37 is a 37-amino-acid peptide produced by human cells — the only cathelicidin humans make. It is released by neutrophils, epithelial cells and skin, and it is part of innate immunity: the fast, general defence that acts before the adaptive immune system has identified anything specific.

Its mechanism is unlike that of an antibiotic. Antibiotics interfere with a specific bacterial process — building a cell wall, making a protein — which is why bacteria can evolve around them by altering the target. LL-37 disrupts the bacterial membrane itself, physically, and there is no single target to alter. This is why antimicrobial peptides are studied as a class where conventional resistance is harder to acquire.

The structural feature that makes it work is worth picturing. The peptide folds into a helix with all its positively charged residues on one face and its water-repelling residues on the other. Bacterial membranes carry a net negative charge; human cell membranes largely do not. The charged face is attracted to the bacterium, the water-repelling face inserts into the membrane, and the structure comes apart.

• Killing without a molecular target: Disrupting a membrane physically means there is no single protein a bacterium can mutate to escape. This is the main argument for antimicrobial peptides as a strategy against resistance.

• Selectivity by surface charge: It distinguishes bacterial from human membranes by their electrical charge rather than by recognising a structure. Selectivity from a physical property rather than a lock and key is unusual and instructive.

• A second, signalling role: Beyond killing bacteria it attracts immune cells and influences tissue repair, acting as a messenger as well as a weapon. One molecule doing both is efficient and complicates interpretation.

• When it contributes to disease: Elevated LL-37 is implicated in rosacea and psoriasis, where it appears to drive inflammation rather than resolve it. A defence molecule that causes harm in excess is a genuinely two-sided subject.

Every cell is wrapped in a membrane two molecules thick, made of lipids with water-loving heads facing out and water-repelling tails facing in. The composition differs between organisms, and one difference matters here: bacterial membranes carry negatively charged lipids on their outer surface, while animal cell membranes keep most of theirs on the inner face.

LL-37 exploits that difference. Folded into a helix, it presents positive charges along one side and water-repelling residues along the other. The positive face is drawn to the negatively charged bacterial surface; once in contact, the water-repelling face slides in among the lipid tails. Enough peptide molecules doing this and the membrane loses integrity and the cell dies. Human membranes, lacking the negative outer charge, attract it far less.

The signalling role runs alongside. The same peptide acts as a chemical attractant for immune cells, influences the migration of cells involved in repair, and modulates the response to bacterial debris. Which of these dominates depends on how much is present — a useful defence at ordinary concentrations, a driver of inflammation at high ones, which is the finding behind its involvement in inflammatory skin conditions.

The fundamentals are solid. Its sequence, structure, membrane mechanism and immune signalling roles are established across a large independent literature, and its involvement in rosacea and psoriasis is supported by work from several groups. This is real, mainstream immunology.

Antimicrobial peptides have proved difficult to translate: they degrade quickly, can affect host cells at higher concentrations, and are expensive to manufacture at scale. It holds no medicines approval and is supplied for laboratory research only. It is the human cathelicidin, fully characterised, and the standard subject for work on membrane-disrupting defence — including the question of why translation has been so hard.

KPV is the other end of the scale — three residues acting inside the cell on a transcription switch, against thirty-seven acting physically on a membrane from outside. Both are called immune peptides and they have almost nothing in common.

Thymosin Alpha-1 works on the adaptive immune system, instructing the cells that build a specific response, where this one belongs to the innate side that acts first.