ERK Signaling Is Essential for Macrophage Development

• Published in: PloS one Vol. 10; no. 10; p. e0140064
• Main Authors: Richardson, Edward T, Shukla, Supriya, Nagy, Nancy, Boom, W Henry, Beck, Rose C, Zhou, Lan, Landreth, Gary E, Harding, Clifford V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-10-2015; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Analysis; Animals; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; c-Kit protein; CD11b antigen; CD16 antigen; CD34 antigen; Cell culture; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cellular signal transduction; Clonal deletion; Colony-stimulating factor; Differentiation; Extracellular signal-regulated kinase; Extracellular signal-regulated kinases; Flox; Gene Deletion; Gene expression; Gene Expression Regulation; Granulocytes - cytology; Granulocytes - metabolism; Growth factors; Hematopoiesis; Hematopoietic stem cells; HIV; Hospitals; Human immunodeficiency virus; Infectious diseases; Kinases; Laboratories; Leukocytes (granulocytic); Leukocytes (neutrophilic); Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - metabolism; Macrophages; Macrophages - cytology; Macrophages - metabolism; MAP Kinase Signaling System; Metabolic pathways; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes; Monocytes - metabolism; Mycobacterium tuberculosis; Myeloid cells; Osteoprogenitor cells; Pathology; Physiological aspects; Precursors; Proteins; Rodents; Signal transduction; Signaling; Stem cell transplantation; Stem cells; Tuberculosis; United States; Cleveland Ohio; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140064

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.