Department of Immunology, Duke University Medical Center, Durham, NC, USA.
Blood. 2011 Jan 13;117(2):618-29. doi: 10.1182/blood-2010-01-265959. Epub 2010 Oct 27.
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.
及时清除炎症部位凋亡的中性粒细胞是巨噬细胞的重要功能；然而，巨噬细胞在稳态条件下维持中性粒细胞稳态的作用尚不清楚。通过条件性地在髓样细胞中删除抗凋亡基因细胞 FLICE 样抑制蛋白 (C-FLIP)，我们生成了一种新型的骨髓基质和边缘区巨噬细胞缺失的小鼠模型。这些小鼠表现出严重的中性粒细胞增多、脾肿大、骨髓外造血、体重减轻以及粒细胞集落刺激因子 (G-CSF) 和 IL-1β的产生增加，但不产生 IL-17。c-FLIP(f/f) LysM-Cre 小鼠表现出循环中性粒细胞清除延迟，表明巨噬细胞不能有效地清除凋亡中性粒细胞，导致产生细胞因子，从而驱动过度的粒细胞生成。此外，体内阻断 G-CSF 而不是 IL-1R 信号转导可挽救这种中性粒细胞增多症，表明在清除凋亡细胞有缺陷的小鼠中，一种依赖 G-CSF、不依赖 IL-1β的途径在促进中性粒细胞生成中发挥作用。
