TY  - JOUR
A1  - Tilstam, Pathricia V.
A1  - Gijbels, Marion J.
A1  - Habbeddine, Mohamed
A1  - Cudejko, Celine
A1  - Asare, Yaw
A1  - Theelen, Wendy
A1  - Zhou, Baixue
A1  - Döring, Yvonne
A1  - Drechsler, Maik
A1  - Pawig, Lukas
A1  - Simsekyilmaz, Sakine
A1  - Koenen, Rory R.
A1  - de Winther, Menno P. J.
A1  - Lawrence, Toby
A1  - Bernhagen, Jürgen
A1  - Zernecke, Alma
A1  - Weber, Christian
A1  - Noels, Heidi
T1  - Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice
JF  - PLOS ONE
N2  - 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.
KW  - NF-KAPPA-B
KW  - regulatory T cells
KW  - indoleamine 2,3-dioxygenase
KW  - dendritic cells
KW  - gene expression
KW  - increases atherosclersosis
KW  - receptor
KW  - inhibition
KW  - pathway
KW  - beta
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117450
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Gil-Pulido, Jesus
A1  - Cochain, Clement
A1  - Lippert, Malte A.
A1  - Schneider, Nicole
A1  - Butt, Elke
A1  - Amézaga, Núria
A1  - Zernecke, Alma
T1  - Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice
JF  - PLoS ONE
N2  - Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α\(^{+}\) and CD103\(^{+}\) DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr\(^{−/-}\))-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α\(^{+}\) and CD103\(^{+}\) antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis.
KW  - atherosclerosis
KW  - dendritic cells
KW  - Batf3
KW  - deficiency
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170535
VL  - 12
IS  - 8
ER  -