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  • Review Article
  • Published:

Emergency granulopoiesis

Nature Reviews Immunology volume 14, pages 302–314 (2014)Cite this article

Subjects

Key Points

  • Emergency granulopoiesis is defined as the well-orchestrated de novo generation of neutrophils in response to systemically disseminated infection. The overall goal of this process is to enhance neutrophil output from the bone marrow to meet the higher demand for neutrophils during severe infection when these cells are consumed in large quantities during the innate immune response.

  • Emergency granulopoiesis can be dissected into three phases: pathogen sensing is followed by translation of this signal into enhanced granulocytic cell production in the bone marrow, and then the subsequent re-establishment of homeostatic steady-state conditions once the infection has been cleared.

  • Pathogen sensing mainly occurs in non-haematopoietic cells through Toll-like receptor signalling and leads to the subsequent initiation of emergency granulopoiesis through the release of granulopoietic cytokines. In addition, pathogen sensing by haematopoietic stem and progenitor cells themselves might contribute to the overall granulopoietic response directly by promoting proliferation and myeloid cell differentiation, and also indirectly through the release of cytokines by early haematopoietic cells that signal in a paracrine and autocrine manner. The biological relevance of direct pathogen sensing by haematopoietic stem and progenitor cells in acute and chronic inflammation remains to be determined.

  • Granulocyte colony-stimulating factor is the major granulopoietic cytokine regulating both steady-state and emergency granulopoiesis. At the transcriptional level, CCAAT-enhancer-binding protein-α (C/EBPα) drives steady-state granulopoiesis, whereas C/EBPβ is the master regulator of emergency granulopoiesis.

  • The mechanisms that restrain emergency granulopoiesis and orchestrate the return to steady-state conditions are incompletely understood but are known to involve suppressor of cytokine signalling proteins.

Abstract

Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.

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Figure 1: The haematopoietic hierarchy.
Figure 2: Local versus systemic bacterial infection.
Figure 3: Direct and indirect pathways for the activation of emergency granulopoiesis.
Figure 4: Signal transduction and transcriptional networks in steady-state and emergency granulopoiesis.
Figure 5: An integrated model of emergency granulopoiesis.

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Acknowledgements

The work in the authors' laboratory is supported by grants from the Swiss National Science Foundation (310030_146528/1), the Promedica Foundation, Switzerland, and the Clinical Research Priority Program of the University of Zürich, Switzerland.

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  1. Division of Hematology, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland

    Markus G. Manz & Steffen Boettcher

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  1. Markus G. Manz
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Correspondence to Markus G. Manz.

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PowerPoint slides

Glossary

Granulocytes

The generic term for neutrophils, eosinophils and basophils, which have in common a granule-rich cytoplasm. Neutrophils make up the vast majority (∼90%) of granulocytes in peripheral blood.

Neutrophilia

A relative or absolute increase in the number of neutrophils in the blood.

Neutrophil extracellular traps

(NETs). These are mainly composed of DNA that is released from neutrophils upon pathogen encounter. NETs have microbicidal activity and bind to pathogens, thereby preventing pathogen dissemination.

Mesenchymal stromal cells

A heterogeneous group of stromal cells found in various tissues that is composed of cells with the developmental potential to generate bone, cartilage and adipose tissue (also historically known as mesenchymal stem cells). Mesenchymal stromal cells in the bone marrow are crucial constituents of the haematopoietic microenvironment, which is often termed the 'haematopoietic stem cell niche'.

Parabiosis

An experimental model system in which two animals (most often mice) are surgically joined to establish a common circulation.

Permissive model of lineage specification

This model proposes that upstream multipotent precursors produce downstream lineage-specific progenitors at a fixed rate that can then be stimulated upon need. Cytokines regulate the proliferation or apoptosis of cells that are already committed to a lineage due to intrinsic developmental programmes.

Instructive model of lineage specification

This model proposes that upstream multipotent precursors produce defined lineage-specific progenitors upon specific need. Cytokines trigger a molecular programme in stem and progenitor cells that induces differentiation to a specific lineage.

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Manz, M., Boettcher, S. Emergency granulopoiesis. Nat Rev Immunol 14, 302–314 (2014). https://doi.org/10.1038/nri3660

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