Abstract
Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of “emergency” granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.
Highlights
C/EBPa and -b play critical roles in regulating the tempo of granulopoiesis
We propose that feedback mechanisms that maintain neutrophil pools in the steady-state play critical roles in the accelerated granulopoiesis associated with inflammation
We have shown that alum induces emergency granulopoiesis via IL-1RI-dependent signals [3]
Summary
C/EBPa and -b play critical roles in regulating the tempo of granulopoiesis. Neutrophil pools in the blood and BM are normally maintained by a granulopoietic process dependent on the C/EBPa transcription factor [1,2]. C/EBPb is thought to facilitate proliferation by myeloid progenitor cells in response to inflammatory growth factors [2], but the extracellular signals that stimulate neutrophil production during inflammatory responses are unclear. C/EBPb2/2 mice, in contrast, exhibit normal numbers of neutrophils in the steady-state, but fail to mount neutrophilias in response to infection or cytokine treatment, implicating C/EBPb as a regulator of emergency granulopoiesis [2]. Growth factors elicited during infections are thought to reduce C/EBPa expression in GMP while increasing C/EBPb expression, and thereby focusing differentiation towards neutrophils while elevating rates of proliferation [2]. The model that has emerged from these observations is that C/EBPa and C/EBPb control distinct pathways of steady-state and emergency granulopoiesis, respectively
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