STAT3 controls myeloid progenitor growth during emergency granulopoiesis.
Granulocyte colony-stimulating factor (G-CSF) mediates "emergency" granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion.
Zhang
Huiyuan
H
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903, USA.
Nguyen-Jackson
Hoainam
H
Panopoulos
Athanasia D
AD
Li
Haiyan S
HS
Murray
Peter J
PJ
Watowich
Stephanie S
SS
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002453:Cell Cycle; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology; D019891:Leukopoiesis; D008089:Listeria monocytogenes / Q000472:pathogenicity; D051379:Mice; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C545013:Cebpb protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor