Increased LL37 in psoriasis and other inflammatory disorders promotes LDL uptake and atherosclerosis
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
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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Research Article Cardiology Dermatology

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.

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 5

Transgenic expression of CAMP enhances the development of atherosclerosis.

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Transgenic expression of CAMP enhances the development of atherosclerosi...
(A–F) Apoe–/– and LL37tg/tg Apoe–/– mice were fed a HFD for 10 weeks. (A) Representative images of the aortic arch. (B and C) Representative en face images of aortas stained with oil red (B) to detect atherosclerotic plaques and quantitation of lesion surface area (C) (n = 13 in Apoe–/– mice, n = 12 in LL37tg/tg Apoe–/– mice). (D and E) Representative images of oil red/hematoxylin-stained aortic sinus sections (D) and quantitation of plaque area (E) (n = 13 in Apoe–/– mice, n = 11 in LL37tg/tg Apoe–/– mice). Scale bar: 500 μm (D). (F) Mouse serum concentrations of total cholesterol and LDL cholesterol (n = 4 per group fed a ND, n = 8 per group fed a HFD, respectively). (G) Coimmunoprecipitation of serum from Apoe–/– mice or LL37tg/tg Apoe–/– mice fed a ND with anti-LL37 and detection with anti-LL37 and anti-apoB. (H) Coimmunoprecipitation of human serum from healthy blood donors with anti-LL37 and detection with anti-LL37 and anti-apoB. (I and J) Representative images of Nile red/LL37–stained plaques (I) and CD68/ LL37-stained plaques (J) in LL37tg/tg Apoe–/– mice. Scale bars: 50 μm (I and J). Original magnification, ×3 (enlarged inset on right in J). (K) Linear regression analysis of human plasma LL37 and PC-oxPL in patients with atherosclerosis (n = 20). Data indicate the mean ± SEM. **P < 0.01 and ****P < 0.0001, by 2 tailed Student’s t test (C and E) or linear regression analysis (K).