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 4

Manganese-dependent superoxide dismutase 2 (SOD2) function is impaired in psoriatic macrophages.

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Manganese-dependent superoxide dismutase 2 (SOD2) function is impaired i...
(A) Mouse BM cell SOD2–derived ROS were labeled using MitoSox and examined by flow cytometry (n = 12/15). (B) qPCR analysis of BMDMs revealed changes in mitochondria-related gene expression (n ≥ 4). (C) Mitochondrial ROS of differentiated macrophages are increased in K14-Rac1V12–/+ BMDM. A representative histogram is shown (n = 12/15). (D) Differentiation levels of BMDMs in the presence of MnCl2, a SOD2 activator, was determined and significantly reduced (n ≥ 11). (E) mRNA expression profile was compared with pre-MnCl2 differentiation conditions using qPCR (n ≥ 5). (F) Since mitochondrial ROS staining does not qualify as an SOD2 activation measurement, SOD2 activity was detected using the SOD assay kit in the presence of potassium cyanide to inhibit SOD1 and SOD3 activity, displaying decreased activity in psoriatic BMDMs, which is rescued to LMC levels when differentiated with MnCl2 and treated with MnTBAP (n ≥ 5). (G and H) Mitochondrial ROS were labeled using MitoSox after treatment with the SOD2 mimetic MnTBAP (12.5 μM) in MnCl2 and control-differentiated LMC and psoriatic BMDM. Mitochondrial ROS were visualized using microscopy after PFA fixation and DAPI nuclei labeling (n = 3) and detected using flow cytometry (n ≥ 5). A representative histogram is shown. (Data are expressed as mean ± SEM; *P < 0.05, **P < 0.005, ***P < 0.0005 indicates significance to LMC control; #P < 0.05 indicates significance to K14-Rac1V12–/+ control; ^P < 0.05 indicates significance between indicated groups; [A, B, C, D, and F] Mann-Whitney test, [E and G] 2-way ANOVA with Bonferroni correction P = 0.01, scale bar: 50 μm) (LMC, littermate control; MnTBAP, Manganese [III] Tetrakis [4-Benzoic Acid] Porphyrin chloride).