Map3k8 Modulates Monocyte State and Atherogenesis in ApoE¿/¿ Mice

Abstract

OBJECTIVE¿ Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-¿R, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology. APPROACH AND RESULTS¿ We show here that Map3k8 deficiency results in smaller numbers of Ly6ChighCD11clow and Ly6ClowCD11chigh monocytes in ApoE¿/¿ mice fed a high-fat diet (HFD). Map3k8¿/¿ApoE¿/¿ monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6ClowCD11chigh monocytes. Map3k8¿/¿ApoE¿/¿ splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency altered cell adhesion and migration in vivo and decreased CCR2 expression, a determinant chemokine receptor for monocyte mobilization, on circulating Ly6ChighCD11clow monocytes. Map3k8¿/¿ApoE¿/¿ mice fed an HFD showed decreased cellular infiltration in the atherosclerotic plaque, with low lipid content. Lesions had similar size after Map3k8+/+ApoE¿/¿ bone marrow transplant into Map3k8¿/¿ApoE¿/¿ and Map3k8+/+ApoE¿/¿ mice fed an HFD, whereas smaller plaques were observed after the transplantation of bone marrow lacking both ApoE and Map3k8. CONCLUSIONS¿ Map3k8 decreases apoptosis of monocytes and enhances CCR2 expression on Ly6ChighCD11clow monocytes of ApoE¿/¿ mice fed an HFD. These findings explain the smaller aortic lesions in ApoE¿/¿ mice with Map3k8¿/¿ApoE¿/¿ bone marrow cells fed an HFD, supporting further studies of Map3k8 as an antiatherosclerotic target.