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Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease

Nature Clinical Practice Rheumatology volume 2, pages 500–510 (2006)Cite this article

Abstract

Recent studies have highlighted the functional capacity of neutrophils as powerful mediators of tissue inflammation. Granule-packaged proteases and reactive oxygen intermediates, which are important for intracellular digestion during phagocytosis, are released from neutrophils during inflammation. In the extracellular environment, neutrophil-derived proteases can cause local tissue damage, but also regulate the activity of cytokines, cytokine receptors and chemokines. Neutrophils can themselves produce an array of inflammatory mediators, including cytokines, chemokines and complement; these cells also express Fc receptors, which can bind and possibly transport immune complexes into the extravascular compartment, as well as activating neutrophils at opsonised surfaces. Blood-borne neutrophils interact with, and then exit through, the endothelium of blood vessels, after which these cells die and must be removed safely. The balance between neutrophil survival and clearance is crucial to the resolution of inflammation. A major regulator of neutrophil production and survival is the cytokine granulocyte colony-stimulating factor (G-CSF). Treatment with G-CSF can exacerbate underlying inflammatory diseases in humans and mice, and G-CSF deficiency is profoundly protective against collagen-induced arthritis in mice. These findings implicate G-CSF as an important proinflammatory cytokine. This article discusses the roles of neutrophils and G-CSF during chronic inflammatory diseases.

Key Points

  • There is extensive tissue infiltration by activated neutrophils in many inflammatory diseases

  • In addition to causing direct tissue damage, activated neutrophils can modulate inflammation via the local production or activation of cytokines, chemokines and complement

  • Neutrophils can be both targets and mediators of autoimmunity

  • Neutrophil apoptosis and clearance is essential for the resolution of inflammation

  • Granulocyte colony-stimulating factor, a key regulator of neutrophil production and survival, can have proinflammatory effects during inflammatory diseases such as rheumatoid arthritis

  • Inhibition of granulocyte colony-stimulating factor might provide a new therapeutic strategy in rheumatoid arthritis and other inflammatory diseases

  • The availability of granulocyte colony-stimulating factor means that, unlike other cytokine antagonists, it could be used to reverse inhibition of granulocyte colony-stimulating factor, if required

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Figure 1: Differentiation, release, recruitment and activation of neutrophils.
Figure 2: Surface receptors and cytoplasmic granules of neutrophils.
Figure 3: Modulation of cytokine and chemokine activity by neutrophil-derived proteases.
Figure 4: Potential neutrophil effector functions at sites of infection or inflammation.
Figure 5: The major biologic actions of G-CSF.

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Acknowledgements

The authors' research is supported by the Reid Charitable Trusts, the Arthritis Foundation of Australia, the Cancer Council of Australia and the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Medical Biology PhD student,

    Jo L Eyles, Andrew W Roberts, Donald Metcalf & Ian P Wicks

  2. Head of the Reid Rheumatology Laboratory in the Division of Autoimmunity and Transplantation,

    Jo L Eyles, Andrew W Roberts, Donald Metcalf & Ian P Wicks

  3. Laboratory Head,

    Jo L Eyles, Andrew W Roberts, Donald Metcalf & Ian P Wicks

  4. Carden Fellow in Cancer Research in the Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Jo L Eyles, Andrew W Roberts, Donald Metcalf & Ian P Wicks

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  1. Jo L Eyles
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Correspondence to Ian P Wicks.

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Competing interests

IP Wicks and JL Eyles are collaborating on the commercial development of G-CSF antagonists. JL Eyes and IP Wicks have declared associations with the following companies/organizations: ABC, CDE, FGH, Murigen Therapeutics and Zenyth Therapeutics. AW Roberts and D Metcalf have declared they have no competing interests.

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Eyles, J., Roberts, A., Metcalf, D. et al. Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease. Nat Rev Rheumatol 2, 500–510 (2006). https://doi.org/10.1038/ncprheum0291

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