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Winkels, Holger; Meiler, Svenja; Smeets, Esther; Lievens, Dirk; Engel, David; Spitz, Charlotte; Bürger, Christina; Rinne, Petteri; Beckers, Linda; Dandl, Angelika; Reim, Sigrid; Ahmadsei, Maiwand; Bossche, Jan van den; Holdt, Lesca M.; Megens, Remco T. A.; Schmitt, Martin M.; Winther, Menno de; Biessen, Eric A.; Borst, Jannie; Faussner, Alexander; Weber, Christian; Lutgens, Esther; Gerdes, Norbert (2017): CD70 limits atherosclerosis and promotes macrophage function. In: Thrombosis and Haemostasis, Vol. 117, No. 1: pp. 164-175
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Abstract

The co-stimulatory molecule CD70 is expressed on activated immune cells and is known to modulate responses of T, B, and NK cells via its receptor CD27. Until now, there is only limited data describing the role of CD70 in atherosclerosis. We observed that ruptured human carotid atherosclerotic plaques displayed higher CD70 expression than stable carotid atherosclerotic plaques, and that CD70 expression in murine atheroma localized to macrophages. Lack of CD70 impaired the inflammatory capacity (e.g. reactive oxygen species and nitric oxide production) of bone marrow-derived macrophages, increased both M1-like and M2-like macrophage markers, and rendered macrophages metabolically inactive and prone to apoptosis. Moreover, CD70-deficient macrophages expressed diminished levels of scavenger receptors and ABC-transporters, impairing uptake of oxidised low-density lipoprotein (oxLDL) and cholesterol efflux, respectively. Hyperlipidaemic Apoe(-/-) mice reconstituted with CD70-deficient bone marrow displayed a profound increase in necrotic core size, plaque area, and number of lesional macrophages as compared to mice receiving control bone marrow. Accordingly, 18 week-old, chow diet-fed CD70-deficient Apoe(-/-) mice displayed larger atheroma characterised by lower cellularity and more advanced plaque phenotype than Apoe(-/-) mice. In conclusion, CD70 promotes macrophage function and viability and is crucial for effective phagocytosis and efflux of oxLDL. Deficiency in CD70 results in more advanced atheroma. Our data suggest that CD70 mitigates atherosclerosis at least in part by modulating macrophage function.