“Emergency” granulopoiesis in G-CSF–deficient mice in response to Candida albicans infection

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein believed to play an important role in regulating granulopoiesis both at steady state and during an “emergency” situation. Generation of G-CSF and G-CSF receptor–deficient mice by gene targeting has demonstrated unequivocally the importance of G-CSF in the regulation of baseline granulopoiesis. This study attempted to define the physiologic role of G-CSF during an emergency situation by challenging a cohort of wild-type and G-CSF–deficient mice with Candida albicans. Interestingly, after infection, G-CSF–deficient mice developed an absolute neutrophilia that was observed both in blood and bone marrow. In addition, 3 days after Candida infection increased numbers of granulocyte-macrophage (GM) and macrophage (M) progenitors were observed in the bone marrow of G-CSF–deficient mice. Of the cytokines surveyed, interleukin (IL)-6 levels in serum were elevated; interestingly, levels of IL-6 were higher and more sustained in G-CSF–deficient mice infected with C albicans than similarly infected wild-type mice. Despite the higher levels of serum IL-6, this cytokine is dispensable for the observed neutrophilia because candida-infected IL-6–deficient mice, or mice simultaneously deficient in G-CSF and IL-6, developed neutrophilia. Similarly, mice lacking both G-CSF and GM-CSF developed absolute neutrophilia and had elevated numbers of GM and M progenitors in the bone marrow; thus, G-CSF and GM-CSF are dispensable for promoting the emergency response to candidal infection.

Signalling through TLR2/MyD88 induces differentiation of murine bone marrow stem and progenitor cells to functional phagocytes in response toCandida albicans

“…This in vivo result correlates with the above described in vitro effect of C. albicans yeast on proliferation and differentiation of HSPCs, suggesting that this phenomenon may contribute to the increased granulopoiesis detected in mice during candidiasis. This mechanism is compatible with the results previously reported by Basu et al. (2000), showing that mice lacking both G‐CSF and GM‐CSF are neutropenic, but upon challenge with C. albicans , they develop a profound neutrophilia; moreover, the C. albicans induced neutrophilia in G‐CSF‐deficient mice is sustained and it is also accompanied by an increase in both precursor and mature neutrophils in bone marrow, indicating that it is not merely due to mobilization of a neutrophil reservoir pool, but involves de novo neutrophil production.…”

Nuclear phospholipid scramblase 1 prolongs the mitotic expansion of granulocyte precursors during G-CSF-induced granulopoiesis

“…However, interpretation of these data to identify the primary impact of PLSCR1 on granulocytic differentiation was limited by the heterogeneous and asynchronous nature of the hematopoietic precursors in bone marrow. Furthermore, complicated networks of cytokines/growth factors in vivo may also compensate for some of the defective response to G-CSF by providing alternative myelopoietic signals [45,46]. Thus, an in vitro cellular model capable of responding to G-CSF and differentiating into mature neutrophils was required to further resolve how PLSCR1 contributes to G-CSF-driven granulopoiesis.…”

Current insights into neutrophil homeostasis

“…The term emergency granulopoiesis was coined when neutropenic G-CSF-deficient mice challenged with microbial compounds through injection of infectious agents were found to be able to build up pronounced neutrophilia. 45 Because of this initial report, several groups have set out to characterize the underlying differences between G-CSFindependent neutrophilia in response to infection and G-CSF-dependent steady-state granulopoiesis.…”