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

[Objective]: Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, 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 Ly6C high CD11c low and Ly6C low CD11c high 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 Ly6C low CD11c high 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 Ly6C high CD11c low 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 Ly6C high CD11c low 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.