@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{BuschWesthofenKochetal.2014,
  author    = {Busch, Martin and Westhofen, Thilo C. and Koch, Miriam and Lutz, Manfred B. and Zernecke, Alma},
  title     = {Dendritic Cell Subset Distributions in the Aorta in Healthy and Atherosclerotic Mice},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {2},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0088452},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119907},
  pages     = {e88452},
  year      = {2014},
  abstract  = {Dendritic cells (DCs) can be sub-divided into various subsets that play specialized roles in priming of adaptive immune responses. Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall and DCs can be found in non-inflamed and diseased arteries. We here performed a systematic analyses of DCs subsets during atherogenesis. Our data indicate that distinct DC subsets can be localized in the vessel wall. In C57BL/6 and low density lipoprotein receptor-deficient (Ldlr-/-) mice, CD11c+ MHCII+ DCs could be discriminated into CD103- CD11b+F4/80+, CD11b+F4/80- and CD11b-F4/80- DCs and CD103+ CD11b-F4/80- DCs. Except for CD103- CD11b- F4/80- DCs, these subsets expanded in high fat diet-fed Ldlr-/- mice. Signal-regulatory protein (Sirp)-α was detected on aortic macrophages, CD11b+ DCs, and partially on CD103- CD11b- F4/80- but not on CD103+ DCs. Notably, in FMS-like tyrosine kinase 3-ligand-deficient (Flt3l-/-) mice, a specific loss of CD103+ DCs but also CD103- CD11b+ F4/80- DCs was evidenced. Aortic CD103+ and CD11b+ F4/80- CD103- DCs may thus belong to conventional rather than monocyte-derived DCs, given their dependence on Flt3L-signalling. CD64, postulated to distinguish macrophages from DCs, could not be detected on DC subsets under physiological conditions, but appeared in a fraction of CD103- CD11b+ F4/80- and CD11b+ F4/80+ cells in atherosclerotic Ldlr-/- mice. The emergence of CD64 expression in atherosclerosis may indicate that CD11b+ F4/80- DCs similar to CD11b+ F4/80+ DCs are at least in part derived from immigrated monocytes during atherosclerotic lesion formation. Our data advance our knowledge about the presence of distinct DC subsets and their accumulation characteristics in atherosclerosis, and may help to assist in future studies aiming at specific DC-based therapeutic strategies for the treatment of chronic vascular inflammation.},
  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}
}
@article{BuschBuschScholzetal.2016,
  author    = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo},
  title     = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology},
  series = {International Journal of Molecular Science},
  volume    = {17},
  journal   = {International Journal of Molecular Science},
  number    = {1},
  issn      = {International Journal of Molecular Science},
  doi       = {10.3390/ijms17010081},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422},
  pages     = {81},
  year      = {2016},
  abstract  = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.},
  language  = {en}
}
@article{HerrmannMuellerOrthetal.2020,
  author    = {Herrmann, Andreas B. and M{\"u}ller, Martha-Lena and Orth, Martin F. and M{\"u}ller, J{\"o}rg P. and Zernecke, Alma and Hochhaus, Andreas and Ernst, Thomas and Butt, Elke and Frietsch, Jochen J.},
  title     = {Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance},
  series = {Journal of Cellular and Molecular Medicine},
  volume    = {24},
  journal   = {Journal of Cellular and Molecular Medicine},
  number    = {5},
  doi       = {10.1111/jcmm.14910},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214122},
  pages     = {2942 -- 2955},
  year      = {2020},
  abstract  = {Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.},
  language  = {en}
}
@article{ButtStempfleListeretal.2020,
  author    = {Butt, Elke and Stempfle, Katrin and Lister, Lorenz and Wolf, Felix and Kraft, Marcella and Herrmann, Andreas B. and Viciano, Cristina Perpina and Weber, Christian and Hochhaus, Andreas and Ernst, Thomas and Hoffmann, Carsten and Zernecke, Alma and Frietsch, Jochen J.},
  title     = {Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia},
  series = {Cells},
  volume    = {9},
  journal   = {Cells},
  number    = {2},
  issn      = {2073-4409},
  doi       = {10.3390/cells9020444},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200638},
  year      = {2020},
  abstract  = {The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.},
  language  = {en}
}