Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis

Abstract

Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, Apoe –/– mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders.

Comparing Multifunctional Viral and Eukaryotic Proteins for Generating Scission Necks in Membranes

“…Membrane budding is a common phenomenon that often takes place in large vesicles, known as “mother” vesicles, and results in the formation of smaller “daughter” vesicles. This process is observed in various cellular processes, such as clathrin-mediated endocytosis, the formation of synaptic vesicles, receptor-mediated endocytosis, and the viral replication cycle, where a small coated pit connects to a large mother vesicle via a neck-like structure. ,− …”

Macrophage Functions in Psoriasis: Lessons from Mouse Models

“…This partly explains why macrophages are involved in the development of psoriasis-related comorbidities [76]. Accordingly, LL-37 antimicrobial peptide has been recently shown to promote low-density lipoprotein (LDL) uptake by macrophages, followed by foam cell formation that promotes atherosclerosis and cardiovascular complications in mice [95]. Moreover, psoriasis-related increase in S100A8/A9 expression by endothelial cells and macrophages was suggested to play a role in the development of cardiovascular complications [41].…”