Regulation of steady-state neutrophil homeostasis by macrophages.
The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steady-state conditions is less well understood. By conditionally deleting the antiapoptotic gene cellular FLICE-like inhibitory protein (C-FLIP) in myeloid cells, we have generated a novel mouse model deficient in marginal zone and bone marrow stromal macrophages. These mice develop severe neutrophilia, splenomegaly, extramedullary hematopoiesis, decreased body weight, and increased production of granulocyte colony-stimulating factor (G-CSF) and IL-1β, but not IL-17. c-FLIP(f/f) LysM-Cre mice exhibit delayed clearance of circulating neutrophils, suggesting that failure of macrophages to efficiently clear apoptotic neutrophils causes production of cytokines that drive excess granulopoiesis. Further, blocking G-CSF but not IL-1R signaling in vivo rescues this neutrophilia, suggesting that a G-CSF-dependent, IL-1β-independent pathway plays a role in promoting neutrophil production in mice with defective clearance of apoptotic cells.
Gordy
Claire
C
Department of Immunology, Duke University Medical Center, Durham, NC, USA.
Pua
Heather
H
Sempowski
Gregory D
GD
He
You-Wen
YW
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency / Q000235:genetics; D002470:Cell Survival; D055879:Gene Knock-In Techniques; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D016179:Granulocyte Colony-Stimulating Factor