title: ERK Signaling Is Essential for Macrophage Development.
abstract: Macrophages depend on colony stimulating factor 1 (also known as M-CSF) for their growth and differentiation, but the requirements for intracellular signals that lead to macrophage differentiation and function remain unclear. M-CSF is known to activate ERK1 and ERK2, but the importance of this signaling pathway in macrophage development is unknown. In these studies, we characterized a novel model of Erk1(-/-) Erk2(flox/flox) Lyz2(Cre/Cre) mice in which the ERK2 isoform is deleted from macrophages in the background of global ERK1 deficiency. Cultures of M-CSF-stimulated bone marrow precursors from these mice yielded reduced numbers of macrophages. Whereas macrophages developing from M-CSF-stimulated bone marrow of Erk2(flox/flox) Lyz2(Cre/Cre) mice showed essentially complete loss of ERK2 expression, the reduced number of macrophages that develop from Erk1(-/-) Erk2(flox/flox) Lyz2(Cre/Cre) bone marrow show retention of ERK2 expression, indicating selective outgrowth of a small proportion of precursors in which Cre-mediated deletion failed to occur. The bone marrow of Erk1(-/-) Erk2(flox/flox) Lyz2(Cre/Cre) mice was enriched for CD11b+ myeloid cells, CD11b(hi) Gr-1(hi) neutrophils, Lin- c-Kit+ Sca-1+ hematopoietic stem cells, and Lin- c-Kit+ CD34+ CD16/32+ granulocyte-macrophage progenitors. Culture of bone marrow Lin- cells under myeloid-stimulating conditions yielded reduced numbers of monocytes. Collectively, these data indicate that the defect in production of macrophages is not due to a reduced number of progenitors, but rather due to reduced ability of progenitors to proliferate and produce macrophages in response to M-CSF-triggered ERK signaling. Macrophages from Erk1(-/-) Erk2(flox/flox) Lyz2(Cre/Cre) bone marrow showed reduced induction of M-CSF-regulated genes that depend on the ERK pathway for their expression. These data demonstrate that ERK1/ERK2 play a critical role in driving M-CSF-dependent proliferation of bone marrow progenitors for production of macrophages.
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Medical Scientist Training Program, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Supriya
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Rose C
authors.initials: RC
authors.lastname: Beck
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis; D020935:MAP Kinase Signaling System; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3