LL-37's role in autoimmunity turns on a physical property rather than a signaling one. The peptide carries a net positive charge near +6 at physiological pH, which lets it bind extracellular self-DNA into condensed complexes that resist nucleases and present nucleic acid to TLR9 in a form and spacing those sensors would normally ignore, driving sustained type I interferon from plasmacytoid dendritic cells. Most causal evidence comes from mouse models and cell culture and the human data are largely observational, so the published record supports LL-37 as an amplifier in specific diseases rather than a proven cause of autoimmunity in general.
LL-37 carries a net positive charge of roughly +6 at physiological pH, which lets it condense extracellular self-DNA into nuclease-resistant complexes that drive sustained type I interferon output from plasmacytoid dendritic cells through TLR9.
Tolerance to self nucleic acids rests less on the immune system telling host DNA from microbial DNA chemically and more on compartmentalization and timing: host DNA stays confined to the nucleus and mitochondria, and whatever escapes is degraded by extracellular nucleases such as DNASE1 and DNASE1L3 long before it reaches the endosomal compartment where TLR9 sits. LL-37 defeats both safeguards at once, which is how a molecule with no signaling function of its own sets off an interferon response.
Small-angle X-ray scattering work reports that LL-37-DNA complexes adopt a regular spacing on the order of 3 to 4 nanometers, close to the dimensions of the TLR9 binding site, which appears to let multiple receptors engage a single particle as a high-avidity signaling unit.
The autoantigen claim rests on direct human T cell evidence, not on inference from expression levels. Lande and colleagues reported in 2014 that circulating and lesional T cells from roughly two thirds of the psoriasis cohort studied proliferate and produce cytokines when stimulated with LL-37, while T cells from healthy donors generally do not. That evidence, plus a link to an inherited risk allele, is what separates psoriasis from every other disease on this list.
In the cohort Lande and colleagues reported in 2014, roughly two thirds of psoriasis patients carried LL-37-reactive T cells, with the CD8 response HLA class I restricted and associated with HLA-Cw6, the strongest known genetic risk allele for the disease.
Neutrophils are the delivery vehicle. A neutrophil undergoing NETosis extrudes decondensed chromatin studded with granule proteins, and LL-37 is among the most abundant of those proteins on the trap, so peptide and self-DNA leave the cell already bound to each other in close to the configuration that activates TLR9. What turns an episodic event into chronic disease is a constant supply paired with failed clearance.
LL-37-DNA complexes released on neutrophil extracellular traps are the leading mechanistic explanation for the interferon-inducible gene signature detectable in the blood of a majority of lupus patients, though serum cathelicidin has no validated cutoff or established clinical use.
Rosacea is not simply a matter of too much cathelicidin. Rosacea skin expresses the precursor at abnormally high levels and cuts it differently, so the peptides that end up in the tissue are not the LL-37 found in normal skin. Gallo's group reported that those fragments, rather than intact LL-37, reproduce rosacea-like erythema and inflammation when injected into mouse skin, which is the strongest causal evidence in this disease and it comes from an animal model.
| Criteria | Normal facial skin | Rosacea skin |
|---|---|---|
| Cathelicidin expression | Low baseline | Abnormally high |
| Kallikrein 5 activity | Held in check by serine protease inhibitors | Elevated, inhibitor levels reduced |
| Peptide species released | Intact LL-37 | Fragments differing in length and sequence |
| Reported vascular effect | None | Vasodilation, endothelial activation, leukocyte chemotaxis |
Kallikrein 5 activity is elevated in rosacea skin, and the cathelicidin fragments it generates, not intact LL-37, reproduce rosacea-like erythema and inflammation when injected into mouse skin.
Compared with psoriasis, the rheumatoid case is suggestive rather than established. LL-37 has been detected in rheumatoid synovial fluid at higher concentrations than in osteoarthritis controls, but reported concentrations vary widely between studies and no threshold carries clinical meaning.
Citrullinated LL-37 has been reported in rheumatoid synovial tissue, but it is not among the established anti-citrullinated protein antibody targets and the evidence has not been replicated at anything like the level of citrullinated vimentin, fibrinogen, or alpha-enolase.
One variable does most of the work: whether free extracellular self-DNA is available for the peptide to bind. Without it, LL-37 behaves as a well-mannered innate effector, binding and neutralizing lipopolysaccharide and promoting epithelial migration and wound closure. Add abundant free DNA, as happens where neutrophils are dying by NETosis or keratinocytes are being damaged, and the identical peptide becomes an interferon-driving adjuvant.
Cathelicidin-knockout mice develop worse dextran sulfate sodium colitis and are more susceptible to skin and gut infection, yet the same animals are protected in imiquimod-driven psoriasis-like models, which places the peptide's sign with the tissue context rather than the molecule.
No single receptor accounts for LL-37's effects, and that fact is itself informative. Formyl peptide receptor 2 is the best-characterized candidate, supported by loss of chemotaxis in the presence of antagonists such as WRW4, but it does not explain most of what the peptide does. That scatter across a GPCR interaction, receptor transactivation, purinergic signaling, cargo delivery, and non-specific membrane effects is a real obstacle for any drug strategy that hopes to block LL-37 signaling at a single point.
LL-37 is not a ligand for TLR9 or TLR7; it delivers DNA and RNA to those sensors in an activating form, acting as carrier and organizer while the receptor responds to the nucleic acid.
Presence is established; function is not. Cathelicidin is detected by immunostaining in macrophage-rich regions of human atherosclerotic plaque and alongside infiltrating neutrophils, reported consistently enough to count as settled, but what it does there rests on mechanistic plausibility and mouse work rather than human causal data.
Cathelicidin is consistently detected in macrophage-rich regions of human atherosclerotic plaque, but the pro-atherogenic reading rests on mouse models expressing CRAMP rather than LL-37, so the cardiovascular link remains a hypothesis under test rather than an accepted one.
The autoimmune risk here follows directly from the mechanism rather than from speculation. If the pathogenic step in psoriasis and lupus is LL-37 binding free self-DNA and delivering it to TLR9, then introducing more LL-37 into a tissue that already contains dying cells or NETs supplies the missing half of that complex. The mechanistic grounds for concern are strong, no controlled trial has tested the question directly, and no cathelicidin-based drug holds marketing approval in the United States or Europe.
LL-37 damages the membranes of human erythrocytes, lymphocytes, and fibroblasts at concentrations similar to those required for its antibacterial activity, and no cathelicidin-based drug holds marketing approval in the United States or Europe.
Sorting the evidence by its source changes the picture considerably. Psoriasis carries direct human tissue observation, human T cell data, and a mechanism reproduced by independent groups in human cells, while atherosclerosis carries presence and mouse models. The defensible statement is that LL-37 is a mechanistically well-supported amplifier in specific diseases and a demonstrated autoantigen in a subset of psoriasis patients, and that broader claims about LL-37 causing autoimmunity outrun the available data.
No targeted human intervention that removes or blocks LL-37 activity specifically has been tested, and the existing psoriasis biologics all act downstream on IL-17, IL-23, or TNF, so their success is compatible with the LL-37 hypothesis without testing it.
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