@article{SoehnleinDrechslerDoeringetal.2013,
  author    = {Soehnlein, Oliver and Drechsler, Maik and D{\"o}ring, Yvonne and Lievens, Dirk and Hartwig, Helene and Kemmerich, Klaus and Ortega-G{\´o}mez, Almudena and Mandl, Manuela and Vijayan, Santosh and Projahn, Delia and Garlichs, Christoph D. and Koenen, Rory R. and Hristov, Mihail and Lutgens, Esther and Zernecke, Alma and Weber, Christian},
  title     = {Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes},
  series = {EMBO Molecular Medicine},
  volume    = {5},
  journal   = {EMBO Molecular Medicine},
  issn      = {1757-4676},
  doi       = {10.1002/emmm.201201717},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122204},
  pages     = {471-481},
  year      = {2013},
  abstract  = {We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.},
  language  = {en}
}
@article{TilstamGijbelsHabbeddineetal.2014,
  author    = {Tilstam, Pathricia V. and Gijbels, Marion J. and Habbeddine, Mohamed and Cudejko, Celine and Asare, Yaw and Theelen, Wendy and Zhou, Baixue and D{\"o}ring, Yvonne and Drechsler, Maik and Pawig, Lukas and Simsekyilmaz, Sakine and Koenen, Rory R. and de Winther, Menno P. J. and Lawrence, Toby and Bernhagen, J{\"u}rgen and Zernecke, Alma and Weber, Christian and Noels, Heidi},
  title     = {Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0087452},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117450},
  pages     = {e87452},
  year      = {2014},
  abstract  = {Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach.},
  language  = {en}
}