Interacting Gaussian curvatures and their role in connecting inflammation and cardiovascular disease*

LL37 is a human cathelicidin innate immune peptide that is implicated in the pathogenesis of autoimmune diseases such as lupus, rosacea, and psoriasis. Recent studies have revealed a substantially increased risk of cardiovascular disease in patients with psoriasis and other inflammatory diseases. Particularly, the severity of psoriasis has been positively correlated with an increased likelihood of developing atherosclerosis. However, the mechanochemical mechanism underlying the association between LL37, inflammatory skin diseases and the increased risk of atherosclerosis remains elusive. In this study, we investigated the role of LL37, a host defense peptide upregulated in skin inflammation, in promoting Low-Density Lipoprotein (LDL) uptake and lipid accumulation in macrophages and endothelial cells. LDLs are spheroidal aggregates organized by apolipoproteins and are rich in positive Gaussian curvature. Using high-resolution Small Angle X-ray Scattering (SAXS) experiments, we showed that the interaction between LDL particles and LL37 leads to a significant increase in the LDL size. We find that LL37 enhances macrophage LDL uptake through receptor-mediated endocytosis. Notably, our results demonstrated that LL37-induced LDL uptake is unique to humans and primates within the cathelicidin antimicrobial gene family and is not observed in other mammals.