title: 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-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.
  
  
  RESULTS
  We show here that Map3k8 deficiency results in smaller numbers of Ly6ChighCD11clowand Ly6ClowCD11chighmonocytes 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 Ly6ClowCD11chighmonocytes. 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 Ly6ChighCD11clowmonocytes. 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 Ly6ChighCD11clowmonocytes 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.
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Sanz-Garcia
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Ángela
authors.initials: Á
authors.lastname: Sánchez
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Constanza
authors.initials: C
authors.lastname: Contreras-Jurado
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Carmela
authors.initials: C
authors.lastname: Cales
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Barranquero
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Marta
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Paula
authors.initials: P
authors.lastname: Escudero
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Maria-Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Jesús
authors.initials: J
authors.lastname: Osada
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.).
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
authors.affiliation: From the Instituto de Investigaciones Biomédicas "Alberto Sols" Madrid, Consejo Superior de Investigaciones Científicas (CSIC-UAM) y Unidad de Biomedicina (UA, CSIC), University of Las Palmas de Gran Canaria, España (C.S.-G., Á.S., C.C.-J., C.C., A.A., S.A.); Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, IISA, University of Zaragoza, España (C.B., J.O.); Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC), Santander, España (M.M., R.M.); and Departmento de Farmacologia, Facultad de Medicina, University of Valencia, INCLIVA, España (P.E., M.-J.S.). salemany@iib.uam.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Alemany
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D039521:CD11c Antigen / Q000378:metabolism; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D039521:CD11c Antigen; C515335:Ccr2 protein, mouse; D016207:Cytokines; C494192:Ly-6C antigen, mouse; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011518:Proto-Oncogene Proteins; D054390:Receptors, CCR2; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
keywords: Toll-like receptors; apoptosis; atherosclerosis; bone marrow; monocytes