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Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis
Yvonne Baumer, … , Martin P. Playford, Nehal N. Mehta
Yvonne Baumer, … , Martin P. Playford, Nehal N. Mehta
Published January 11, 2018
Citation Information: JCI Insight. 2018;3(1):e97179. https://doi.org/10.1172/jci.insight.97179.
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Research Article Cardiology Inflammation

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

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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 1

Overexpression of constitutive active Rac1 V12 in keratinocytes induces psoriasis accompanied by systemic chronic inflammation.

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Overexpression of constitutive active Rac1 V12 in keratinocytes induces ...
(A) Severity of psoriasis phenotype based on visible symptoms was determined on a 0–5 scale. Severity levels of 2 and 3 accounted for the majority of all animals (n = 117). (B) Blood cell composition differences were determined by flow cytometry. Decreased levels of B cells, T cells, classical (Ly6Chi), and nonclassical (Ly6Clo) monocytes were observed, while the neutrophil population increased (n = 8/9). (C) Chronic inflammation was detected by measuring plasma cytokine levels in adolescent (younger than 10 weeks) and adult (older than 12 weeks) K14-Rac1V12–/+ mice and their LMC. Increased levels of all proinflammatory cytokines were detected (n > 5). (D) Transmission electron microscopy of mouse aortas showed infiltration of myeloid cells into the subendothelial space (n = 3/3) and the tunica media, which was confirmed by flow cytometry (E) of Liberase-digested aortas (n = 10/13). Neutrophils, resident (res) DCs and especially macrophages are showing the most significant changes. (F) Plasma from adult LMC and K14-Rac1V12–/+ mice were used to determine MCP-1 and RANTES chemokine levels (n = 27/38). (Data are expressed as mean ± SEM, n = LMC/K14-Rac1V12–/+; Mann-Whitney test P < 0.05) (LMC, littermate control; EC, endothelial cell; E, elastin layer; C, collagen; SMC, smooth muscle cell; L/M/MØ, lymphoid or myeloid cell; MØ, macrophages; conv, conventional; res, resident; myl, myeloid; Monos, monocytes; M0, macrophages; MCP-1 (CCL2), monocyte chemoattractant protein 1. Scale bar: 5µm. *P < 0.05, **P < 0.0005.

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