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Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis
Yoshiyuki Nakamura, … , Gerard C.L. Wong, Richard L. Gallo
Yoshiyuki Nakamura, … , Gerard C.L. Wong, Richard L. Gallo
Published January 9, 2024
Citation Information: J Clin Invest. 2024;134(5):e172578. https://doi.org/10.1172/JCI172578.
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Research Article Cardiology Dermatology Article has an altmetric score of 16

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

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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.

Authors

Yoshiyuki Nakamura, Nikhil N. Kulkarni, Toshiya Takahashi, Haleh Alimohamadi, Tatsuya Dokoshi, Edward Liu, Michael Shia, Tomofumi Numata, Elizabeth W.C. Luo, Adrian F. Gombart, Xiaohong Yang, Patrick Secrest, Philip L.S.M. Gordts, Sotirios Tsimikas, Gerard C.L. Wong, Richard L. Gallo

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Figure 1

LL37 promotes LDL entry into cells.

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LL37 promotes LDL entry into cells.
(A) Visualization of pHrodo-LDL in T...
(A) Visualization of pHrodo-LDL in THP-1 macrophages in the absence or presence of LL37. (B) Total fluorescence of pHrodo-LDL in THP-1 macrophages treated as in A (n = 5 per group). (C) FACS analysis and (D) proportion of CD45+ pHrodo-LDL+ THP-1 cells after treatment with LL37 (n = 6 per group). (E) Comparison of pHrodo-LDL or pHrodo-oxLDL uptake in the presence or absence of LL37 in THP-1 macrophages (n = 6–7 per group). (F) Dose-dependent uptake of pHrodo-LDL at the indicated concentrations of LL37 in THP-1 macrophages (n = 4 per concentration). (G and H) Uptake of pHrodo-LDL into HMDMs (n = 3 per group) (G), primary murine peritoneal macrophages (n = 5 per group) (H), HUVECs (n = 5 per group) (I), HAoECs (n = 5 per group) (J), and EA.hy926 endothelial cells (n = 4 per group) (K) treated with LL37. (L) Representative images of Dil-LDL uptake (red) and LL37 (green) in mouse aortas treated with LL37. White dotted lines outline the endothelial layer. (M) Proportion of positive fluorescence areas for Dil-LDL in aortic endothelium in presence and absence of LL37. Scales bars: 50 μm (A and L). Data indicate mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed Student’s t test (Student’s t test relative to no treatment in F).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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