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

Carlos Sanz-Garcia, Ángela Sánchez, Constanza Contreras-Jurado, Carmela Cales, Cristina Barranquero, Marta Muñoz, Ramón Merino, Paula Escudero, Maria-Jesús Sanz, Jesús Osada, Ana Aranda, Susana Alemany
2016 Arteriosclerosis, Thrombosis and Vascular Biology  
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.
more » ... oach 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. (P.E., M.-J.S.). The online-only Data Supplement is available with this article at
doi:10.1161/atvbaha.116.308528 pmid:27856455 fatcat:jnwmmuvafnbjddxbsqbnspnibm