STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils.
Granulocyte colony-stimulating factor (G-CSF) is essential for the host response to bacterial infection by controlling neutrophil production in the bone marrow. The G-CSF receptor (G-CSFR) activates the Jak/STAT pathway, although little is understood about how these signals regulate basal and stress-induced granulopoiesis. We examined STAT3 function in granulocytes using a bone marrow conditional knockout mouse model. Our results show that STAT3 has a crucial role in emergency granulopoiesis and mature neutrophil function. STAT3-deficient mice have an aberrant response to G-CSF in vivo, characterized by failure to accumulate immature granulocytes and an increased ratio of mature to immature neutrophils in the bone marrow, peripheral blood, and spleen. Acute neutrophil mobilization is impaired in STAT3-deficient mice as judged by their failure to up-regulate circulating neutrophils following short-term G-CSF exposure. STAT3 also controls neutrophil chemotactic responses to natural ligands for CXCR2 and regulates the magnitude of chemoattractant-induced actin polymerization. These functions of STAT3 are independent of its principal target gene Socs3, which encodes a crucial feedback inhibitor of cytokine signaling. Our results demonstrate the existence of distinct STAT3 target pathways in neutrophils required for granulopoiesis and innate immunity.
Panopoulos
Athanasia D
AD
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, PO Box 301402, Unit 902, Houston, TX 77030-1903, USA.
Zhang
Ling
L
Snow
Jonathan W
JW
Jones
Daniel M
DM
Smith
Amber M
AM
El Kasmi
Karim C
KC
Liu
Fulu
F
Goldsmith
Mark A
MA
Link
Daniel C
DC
Murray
Peter J
PJ
Watowich
Stephanie S
SS
D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016179:Granulocyte Colony-Stimulating Factor