Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis

Abstract

Objective The IκB kinase (IKK) is an enzyme complex that initiates the NF-κB transcription factor cascade, which is important in regulating multiple cellular responses. IKK alpha (IKKα) is directly associated with two major pro-survival pathways, PI3K/Akt and NF-κB, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKKα signaling on macrophage survival and atherogenesis remains unclear. Approach and Results Here we demonstrate that genetic IKKα deficiency, as well as pharmacologic inhibition of IKK, in mouse macrophages significantly reduces Akt S473 phosphorylation, which is accompanied by suppression of mTORC2 signaling. Moreover, IKKα null macrophages treated with lipotoxic palmitic acid exhibited early exhaustion of Akt signaling compared to WT cells. This was accompanied by a dramatic decrease in the resistance of IKKα−/− monocytes and macrophages to different pro-apoptotic stimuli compared to WT cells. In vivo, IKKα deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male LDLR−/− mice reconstituted with IKKα−/− hematopoietic cells and fed with the Western diet for 8 weeks compared to control LDLR−/− mice transplanted with WT cells. Conclusions Hematopoietic IKKα deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis.

PKB/Akt-dependent regulation of inflammation in cancer

“…Mechanistically, PKB mediates macrophage survival by cross-talking with NF-κB, p38 MAPK and antiapoptotic signals mediated by Mcl1 and Bcl-xL [98][99][100]. Notably, IKK deficiency in macrophages results in decreased viability accompanied with reduced activation of PKB [101], indicating a potential feedback between PKB-IKK/NF-κB in the regulation of macrophage survival.…”

Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis

“…Interestingly, both genetic deficiency of IKK α and pharmacological inhibition of IKK α suppressed Akt phosphorylation in macrophages. 56 Transplantation studies revealed that loss of IKK α in the hematopoietic cells of Ldlr −/− mice was associated with reduced atherosclerotic lesion size, and the lesions displayed increased numbers of apoptotic macrophages compared with control mice transplanted with WT cells. 56 Tilstam et al have reported that knock-in of a non-activatable IKK α kinase (Ikk α AA/AA) mutant in the bone marrow of Apoe −/− mice influenced hematopoiesis but not atherosclerosis.…”

“…56 Transplantation studies revealed that loss of IKK α in the hematopoietic cells of Ldlr −/− mice was associated with reduced atherosclerotic lesion size, and the lesions displayed increased numbers of apoptotic macrophages compared with control mice transplanted with WT cells. 56 Tilstam et al have reported that knock-in of a non-activatable IKK α kinase (Ikk α AA/AA) mutant in the bone marrow of Apoe −/− mice influenced hematopoiesis but not atherosclerosis. 57 However, it is important to note that IKK α activity was not abolished in these Ikk α AA/AA mice, 57 as evidenced by a lack of morphogenic defects and downstream signaling effects specific to loss of IKK α in the original descriptions.…”

Macrophages

“…The same group reported that inhibition of IKKα (involved in alternative NF-κB activation) or its deletion in macrophages limits cell survival, presumably through suppression of mTORC2-mediated AKT S473 phosphorylation, while enhancing macrophage inflammatory status. Moreover, deletion of IKKα in bone marrowderived cells reduces early atherosclerosis in Ldlr −/− mice, 64 further supporting a role for macrophage apoptosis in limiting the development of early lesions. However, IKKα deletion profoundly affects T-and B-cell development and functions, which may also account for the atheroprotective effect.…”