The Ikk? kinase, a subunit of the NF-?B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikk?-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk? mutant knock-in on haematopoiesis and atherosclerosis in mice.Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikk? gene (Ikk?(AA/AA)Apoe(-/-) ) or with Ikk?(+/+)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?(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?(AA/AA)Apoe(-/-) vs Ikk?(+/+)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?(AA/AA)Apoe(-/-) vs Ikk?(+/+)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-? or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable.Our data reveal an important and previously unrecognized role of haematopoietic Ikk? kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikk?(AA) mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikk? in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikk? kinase activity alone does not represent a therapeutic approach.     «

The Ikk? kinase, a subunit of the NF-?B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikk?-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk? mutant knock-in on haematopoiesis and atherosclerosis in mice.Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant...     »