Regulation of steady-state neutrophil homeostasis by macrophages

C Gordy, H Pua, GD Sempowski… - Blood, The Journal of …, 2011 - ashpublications.org
C Gordy, H Pua, GD Sempowski, YW He
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
Abstract
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-FLIPf/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.
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