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Tilstam, Pathricia V.; Gijbels, Marion J.; Habbeddine, Mohamed; Cudejko, Céline; Asare, Yaw; Theelen, Wendy; Zhou, Baixue; Döring, Yvonne; Drechsler, Maik; Pawig, Lukas; Simsekyilmaz, Sakine; Koenen, Rory R.; de Winther, Menno P. J.; Lawrence, Toby; Bernhagen, Jürgen; Zernecke, Alma; Weber, Christian; Noels, Heidi (2014): Bone Marrow-Specific Knock-In of a Non-Activatable Ikk alpha Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice.
In: PLOS ONE 9(2), e87452
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Abstract

Background: The Ikk alpha 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 Ikk alpha-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 Ikk alpha gene (Ikk alpha(AA/AA) Apoe(-/-)) or with Ikk alpha(+/+) 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 Ikk alpha(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 Ikk alpha(AA/AA) Apoe(-/-) vs Ikk alpha(+/+) 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 Ikk alpha(AA/AA) Apoe(-/-) vs Ikk alpha(+/+) 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-alpha 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 Ikk alpha kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikk alpha AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikk alpha in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikka kinase activity alone does not represent a therapeutic approach.