Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis
Yvonne Baumer, Qimin Ng, Gregory E. Sanda, Amit K. Dey, Heather L. Teague, Alexander V. Sorokin, Pradeep K. Dagur, Joanna I. Silverman, Charlotte L. Harrington, Justin A. Rodante, Shawn M. Rose, Nevin J. Varghese, Agastya D. Belur, Aditya Goyal, Joel M. Gelfand, Danielle A. Springer, Christopher K.E. Bleck, Crystal L. Thomas, Zu-Xi Yu, Mårten C.G. Winge, Howard S. Kruth, M. Peter Marinkovich, Aditya A. Joshi, Martin P. Playford, Nehal N. Mehta
Yvonne Baumer, Qimin Ng, Gregory E. Sanda, Amit K. Dey, Heather L. Teague, Alexander V. Sorokin, Pradeep K. Dagur, Joanna I. Silverman, Charlotte L. Harrington, Justin A. Rodante, Shawn M. Rose, Nevin J. Varghese, Agastya D. Belur, Aditya Goyal, Joel M. Gelfand, Danielle A. Springer, Christopher K.E. Bleck, Crystal L. Thomas, Zu-Xi Yu, Mårten C.G. Winge, Howard S. Kruth, M. Peter Marinkovich, Aditya A. Joshi, Martin P. Playford, Nehal N. Mehta
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Research Article Cardiology Inflammation

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

Abstract

Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.

Authors

Yvonne Baumer, Qimin Ng, Gregory E. Sanda, Amit K. Dey, Heather L. Teague, Alexander V. Sorokin, Pradeep K. Dagur, Joanna I. Silverman, Charlotte L. Harrington, Justin A. Rodante, Shawn M. Rose, Nevin J. Varghese, Agastya D. Belur, Aditya Goyal, Joel M. Gelfand, Danielle A. Springer, Christopher K.E. Bleck, Crystal L. Thomas, Zu-Xi Yu, Mårten C.G. Winge, Howard S. Kruth, M. Peter Marinkovich, Aditya A. Joshi, Martin P. Playford, Nehal N. Mehta

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Figure 5

Manganese-dependent superoxide dismutase 2 (SOD2) is a key regulator in psoriasis-induced proatherosclerotic macrophage reprogramming.

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Manganese-dependent superoxide dismutase 2 (SOD2) is a key regulator in ...
BMDM were isolated from LMC and K14-Rac1V12–/+ mice. Cells were differentiated in the absence or presence of 5 μM MnCl2. Additionally, sets of BMDMs were pretreated with 12.5 μM MnTBAP, a SOD2 mimetic, before conducting the experiment. (A) Apoptosis and necrosis in BMDMs was determined using flow cytometry. Results of early apoptotic events under baseline and 50 μg/ml AcLDL-treated conditions (24h) displays a significant reduction in K14-Rac1V12–/+ BMDMs differentiated in the presence of Manganese (n ≥ 4). Modified lipid uptake (B), foam cell formation (C), and cholesterol efflux (D) experiments were performed in the presence of MnCl2 or MnTBAP using control and MnCl2 differentiated BMDMs (n ≥ 5). (E) BMDMs were treated with 50 μg/ml DiI-AcLDL (red) for 24h and nuclei labeled with DAPI (blue) to visualize AcLDL cholesterol crystal formation (arrows indicated CC, arrowheads indicate large densely lipid packed intracellular areas, representative images of total n = 3; scale bar: 50 µm). (F) CC were visualized with a polarized light microscope and quantified using ImageJ under baseline and 50 μg/ml AcLDL treatment conditions (n ≥ 5). (Data are expressed as mean ± SEM; 2-way ANOVA with Bonferroni correction [A, D, and F] P < 0.007, [B and C] ^/#P < 0.01, ^^/##P < 0.005, ^^^/###P < 0.0005) (MnCl2, Manganese chloride; LMC, littermate control; MnTBAP, Manganese [III] Tetrakis [4-Benzoic Acid] Porphyrin chloride; ROS, reactive oxygen species; FC, foam cell formation; Ac, acetylated; LDL, low-density lipoprotein; MFI, median fluorescence intensity).