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. 2019 Feb 5;29(2):475-487.e7.
doi: 10.1016/j.cmet.2018.10.006. Epub 2018 Nov 8.

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis

Li-Hao Huang  1 , Bernd H Zinselmeyer  1 , Chih-Hao Chang  1 , Brian T Saunders  1 , Andrew Elvington  1 , Osamu Baba  1 , Thomas J Broekelmann  2 , Lina Qi  1 , Joseph S Rueve  1 , Melody A Swartz  3 , Brian S Kim  4 , Robert P Mecham  2 , Helge Wiig  5 , Michael J Thomas  6 , Mary G Sorci-Thomas  7 , Gwendalyn J Randolph  8
Affiliations

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis

Li-Hao Huang et al. Cell Metab. .

Abstract

Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.

Keywords: Th17 immunity; artery; atherosclerosis; autoimmunity; collagen; cytokines; extracellular matrix; fibrosis; interstitial transport; skin.

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Conflict of interest statement

DECLARATION OF INTERESTS

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Characterization of cell and molecular trafficking out of the dermis in experimental psoriasis.
(A) H&E staining of ear and back skin with (right) or without (left) IMQ treatment for 14 days; n=5 mice per group. Scale bar is 10μm. (B) Ear thickness on the left (L) or right (R) ear as a function of whether IMQ was applied for 14 days to that ear or not; n=4–5 per group. (C) Control or IMQ-treated (14 days) recipient mice were intradermally-injected with interstitial HDL + human albumin from control or IMQ-treated (14 days) TghApoA-I donor mice and percent transport of each was assessed; n=3 mice per group. (D) FITC skin painting to assess dendritic cell mobilization to lymph nodes in mice that were treated or not with IMQ (14 days) on both ears; n=7–8 mice per group. (E) Representative frames and graphed summary from intravital imaging to quantify lymph flow. n=5 mice per group. (F) Quantification of insoluble collagen and fragments derived from collagen crosslinks from the mouse back flank skin from mice that were treated with or without IMQ on the ears for 14 days; n=5–8 per group. All data are mean ± SEM. (**P< 0.01; ***P< 0.001).
Figure 2.
Figure 2.. PGA1 is useful to study HDL trafficking from skin to plasma.
(A) The hind flank of mice was shaved and photoactivated. Fluorescence of plasma, with blank plasma background subtracted, is plotted from cohorts of mice that included 405 nm light-treated WT mice with or without AAV8-PGA1 infection. (B) Fluorescence of plasma is shown over a time course after photoactivating back skin; n=11–13 per group. (C) The fluorescence of plasma 2 h post photoactivation; n=3–23 per group. Data are mean ± SEM. (*P< 0.05; **P<0.01).
Figure 3.
Figure 3.. IMQ-induced experimental psoriasis in mice inhibits HDL transport from skin and prevents its recirculation to distal tissues
WT pCAG-PGA1 mice with or without IMQ treatment applied to ears for 14 days were photoactivated on their back flank skin, and the fluorescence of plasma (A), or interstitial fluid (B) from the area where photoactivation occurred, 2 h post photoactivation was measured; n=12–28 mice per group for (A); n=4–6 per group for (B). (C) Fluorescence of plasma from PGA1KI/+ mice with or without IMQ treatment for 14 days were compared 2, 4, and 8 h post photoactivation (n=4–6 mice per group). (D-E) Photoactivation experiments as in panel A, but with analysis of a time course of 1 versus 2 weeks of daily IMQ treatment on both ears (D). Insoluble collagen was assessed at each endpoint (E); N= 9–14 in these two panels, carried out over the course of 4 independent experiments. (F) At the end of experiments shown in panel C, following photoactivation of PGA1KI/+ skin at 4 or 8 h, interstitial fluid from the heart or skeletal muscle was collected and fluorescence intensity above baseline values in WT mice was plotted; n=4–6 mice per group.
Figure 4.
Figure 4.. Effect of experimental psoriasis on arterial stiffness, collagen accumulation, HDL trafficking through the artery wall, and atherosclerosis
(A) Quantification of insoluble collagen of the heart or the artery from mice that were treated with or without IMQ on the ears for 14 days, or 14 days followed by another 14-day chase; n=5–9 hearts per group. Right panels show trichrome staining of glycolmethacrylate-embedded sections of the carotid artery wall. Scale bar, for both images, is 50 μm. (B) Augmentation pressure was dynamically assessed after surgical placement of a catheter in the carotid artery of mice treated or not with IMQ (with or without chase). N=5–10 mice per condition. (C) The right common carotid artery of PGA1KI/+ mice was photoactivated and plasma fluorescence determined 2 h after photoactivation; some PGA1KI/+ mice were treated with IMQ on both ears for 14 days, with or without another 14 days chase prior to photoactivation. Some groups also received anti-IL-17 neutralizing mAb during the experiment. N=8–14 mice per group. (D-E) apoE−/− mice were treated or not (baseline) with IMQ daily for 3 weeks after having received anti-IL17 neutralizing mAb or isotype control mAb (panel D) or BAPN or vehicle control (panel E). Aortic arch disease was assessed by the percent of en face aorta that was oil red O positive. N=5–10 mice per group. For all panels, data are mean ± SEM. (*P< 0.05; **P<0.01, ***P<0.005).
Figure 5.
Figure 5.. Role of collagen density influencing molecular transport as a function of molecular mass and interstitial volume.
(A) Nondenaturing gel and immunoblot analysis to assess Stokes radius of interstitial PGA1-derived HDL and the effect of imiquimod treatment, compared with human plasma HDL or interstitial HDL from hApoA1 transgenic mice. Standards marked in right lane. (B-C) FIB-SEM images of dermal back skin from mice treated on the ear without (B) or with (C) IMQ for 14 days. (D) Quantification of interfibrillar volume remaining after collagen fibril volume is accounted for in 3-dimensional analysis of FIB-SEM images. N= 2 mice / group, with 500 random cubes analyzed for interfibrillar volume for each of the two samples, with combined data representing 1000 volume samples and plotted as mean ± SEM. (E) Percent transport of IgA or IgM to plasma after injection of fluorescence-labeled IgA or IgM in the back skin of control or imiquimod-treated mice (14 days on both ears). Similar assay as in panel B for human plasma LDL and albumin. N = 5 per group. (F) Hydroxyproline assay on back skin from PGA1KI/+ mice treated 14 days with or without IMQ on both ears, using vehicle or BAPN as an accompanying treatment during this same period. (G) Fluorescence intensity in plasma 2 h after photoactivation of back skin in mice from panel E; N = 7–8 mice / group for panels (E) and (F). All data are mean ± SEM (* P< 0.05, **P < 0.01, *** P< 0.001).
Figure 6.
Figure 6.. IL-17 and CD4+ T cells govern HDL transport and abrogate procollagen production in distal back skin of IMQ-treated mice
PGA1 transport was analyzed after photoactivation of back skin from mice treated or not with IMQ and other antibodies. Fluorescence of plasma 2 h post photoactivation (A) or insoluble collagen in the back skin (B); n=8 mice per group. (C) Flow cytometry single-cell suspensions, pregated on CD45+CD4+TCRβ+ cells, from WT back skin, treated with or without IMQ on both ears for 0, 3 or 9 days plus antibodies as indicated; n=3 mice per group. (D) Dermis (top) or back skin (bottom) treated with IMQ for 14 days analyzed for various gene expression by quantitative RT-PCR; n=7–10 mice per group. (E) Back skin dermis was solubilized in acid and immunoblotted with anti-collagen I antibody to identify procollagen I (Procol I) or extractable processed collagen I (Col I). n=5–12 samples per group. (F) Collagen assay (left) and HDL trafficking (right) analyzed in plasma 2 h after photoactivation of the back skin from mice treated or not with IMQ in the presence or absence of FTY720; N=8–11. All data, mean ± SEM (* P< 0.05, **P < 0.01, *** P< 0.001). Color codes defined in legend apply to all panels in the figure.
Figure 7.
Figure 7.. Impact of genetic loss of T cells on local skin inflammation and HDL trafficking from distal skin
Representative histological analysis (H&E) of ear section from RAG1 KO mouse that was treated with IMQ for 14 days (A). Scale bar, 200 m. (B) Ear thickness was assessed in various strains of mice indicated by color codes; n=4–8. (C) Effect of anti-CD4 mAb compared with genetic absence of T cells on HDL trafficking from skin to plasma, measured using 2-h photoactivation from the back skin of WT mice infected with pCAG-PGA1 and treated with IMQ (or not); n=4–8 mice per group. Data are mean ± SEM (*P< 0.05, **P < 0.01, ***P< 0.001). Color codes defined in legend apply to all panels in the figure.
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