The antimicrobial peptide LL37, elevated in psoriasis and other inflammatory conditions, promotes cholesterol uptake in immune cells and accelerates atherosclerosis — providing a molecular explanation for why these patients have higher heart disease risk.
Human-specific cardiovascular riskLL37's ability to promote LDL uptake and atherosclerosis is unique to humans and some primates — mouse and rabbit cathelicidins don't have this effect, which may be why the link was missed in animal studies.
What the researchers found
LL37 enhanced LDL uptake in macrophages through three receptors: LDLR, SR-B1, and CD36. This increased cytosolic cholesterol in macrophages and altered lipid metabolism gene expression in ways consistent with cholesterol overloading — the key process driving foam cell formation and atherosclerotic plaque development.
Structural analysis using synchrotron x-ray scattering revealed how LL37 binds LDL particles and facilitates receptor interactions. Critically, this LDL uptake function is unique to human and some primate cathelicidins — it was not observed with mouse or rabbit versions of the peptide, which may explain why standard animal models haven't captured this mechanism. ApoE-knockout mice engineered to express human LL37 developed larger atherosclerotic plaques than controls. In humans with cardiovascular disease, plasma LL37 levels positively correlated with oxidized phospholipids on apolipoprotein B — a validated biomarker of atherosclerotic disease.
Why it matters
This study solves a clinical mystery that has puzzled cardiologists and dermatologists for years: why do patients with psoriasis, lupus, and other inflammatory conditions develop heart disease at much higher rates? The answer involves a peptide that the immune system overproduces during chronic inflammation — creating an unexpected bridge between the innate immune system and cardiovascular disease. This could lead to new biomarkers for heart disease risk in inflammatory conditions and potential therapeutic targets.
How the study worked
This was a multi-approach translational study combining in vitro cell biology (macrophage LDL uptake assays), structural biology (synchrotron small-angle x-ray scattering of LL37-LDL complexes), comparative biology (testing cathelicidins from humans, primates, mice, and rabbits), in vivo atherosclerosis modeling (ApoE-knockout mice expressing human LL37), and clinical correlation (measuring LL37 and OxPL-apoB in human cardiovascular disease patients). Published in the Journal of Clinical Investigation.
What this study cannot tell us
The in vivo atherosclerosis data comes from a mouse model (ApoE-knockout mice), which, while standard, does not perfectly replicate human atherosclerosis. The human correlation between LL37 and OxPL-apoB was observational and cannot prove causation. The study demonstrated the mechanism in macrophages but did not show that blocking LL37 reduces atherosclerosis. The species-specific nature of the finding (human LL37 only) means that decades of mouse cathelicidin research may have missed this pathway entirely.
How to read the evidence
This is a mechanistic translational study published in the Journal of Clinical Investigation, combining in vitro, structural, animal model, and human correlational data. The multi-level evidence is compelling for the mechanism, though the clinical implications remain to be validated in interventional studies.
When this study was published
Published in 2024, this is a very recent study that provides a novel mechanistic explanation for a long-observed clinical association between inflammatory diseases and cardiovascular risk.
The bigger picture
LL37 is one of the most studied antimicrobial peptides in humans — it's known for its role in fighting infections, modulating inflammation, and wound healing. This study reveals a dark side: the same peptide that protects against infection may drive cardiovascular disease when chronically elevated. This finding sits at the intersection of innate immunity, lipid biology, and cardiovascular medicine, and could reshape how we think about the cardiovascular risk of chronic inflammatory diseases. It also raises questions about the safety of therapeutic approaches that aim to boost LL37 for antimicrobial purposes.
Questions still open
- Could blocking LL37's interaction with LDL reduce cardiovascular risk in patients with chronic inflammatory conditions?
- Should LL37 levels be measured as a cardiovascular risk biomarker in patients with psoriasis, lupus, or other inflammatory diseases?
- Does treating the underlying inflammatory condition (e.g., with biologics for psoriasis) reduce LL37 levels enough to lower cardiovascular risk?
Common questions
What is LL37 and why does it matter for heart disease?
Should people with psoriasis be more concerned about heart disease?
Read the original research
Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis.
The Journal of clinical investigation, 134(5)
Citation
Nakamura, Yoshiyuki; Kulkarni, Nikhil N; Takahashi, Toshiya; Alimohamadi, Haleh; Dokoshi, Tatsuya; Liu, Edward; Shia, Michael; Numata, Tomofumi; Luo, Elizabeth Wc; Gombart, Adrian F; Yang, Xiaohong; Secrest, Patrick; Gordts, Philip Lsm; Tsimikas, Sotirios; Wong, Gerard Cl; Gallo, Richard L. (2024). Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis.. The Journal of clinical investigation, 134(5). https://doi.org/10.1172/JCI172578