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  • Review Article
  • Published:

Colony-stimulating factors in inflammation and autoimmunity

Key Points

  • Colony-stimulating factors (CSFs) — granulocyte/macrophage CSF (GM-CSF), macrophage CSF (M-CSF) and granulocyte CSF (G-CSF) — have wider functions than their original in vitro definition as haematopoietic-cell growth factors.

  • Recent extensive animal data indicate that CSF depletion provides benefit in many inflammatory and/or autoimmune conditions.

  • Early-phase clinical trials targeting GM-CSF and M-CSF have commenced.

  • The distinct biological properties of the CSFs offer specific targeting opportunities, but with some associated risks.

  • Information about the background biology of the CSFs is required to predict the probable specific outcomes of CSF blockade.

  • There are several outstanding questions regarding CSF biology that need to be addressed to aid the design of future clinical trials.

Abstract

Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.

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Figure 1: The structures of CSF receptors.
Figure 2: The main functions of GM-CSF and M-CSF.
Figure 3: Macrophage-driven inflammation: a state of 'M-CSF resistance' or compromised M-CSF-receptor signalling.
Figure 4: Proposed pro-inflammatory 'CSF network'.

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Acknowledgements

I would like to thank C. Manthey, A. Nash, E. R. Stanley and A. Lopez for valuable discussions, and R. Sallay and J. Jackson for typing of the manuscript and figure preparation, respectively. I am supported by a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia. Owing to size limitations, this Review can cover only some of the CSF literature that has led to the clinical trials, and the reader will need to refer to other articles for additional information on CSF biology. My apologies are extended to the many authors whose work could not be cited.

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John Hamilton is employed by the University of Melbourne, Australia, which has licensed technology in this area to MorphoSys AG.

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Glossary

Priming

Optimal macrophage activation often requires exposure to at least two signals, such as priming by a cytokine (for example, IFNγ) and further stimulation or amplification by a microbial product (for example, LPS).

Macrophage polarization

Macrophages respond to diverse microenvironmental signals and as a result have been classified as being polarized into a spectrum of M1 to M2 phenotypes. They are classically activated towards the M1 phenotype by microbial products or IFNγ and can thereby eradicate invading organisms and promote type I immune responses; alternative activation by stimulation with IL-4, IL-13 or IL-10 drives macrophages towards the M2 phenotype, which is characterized by hyporesponsiveness to pro-inflammatory stimuli and involvement in debris scavenging, angiogenesis, tissue remodelling, wound healing and the promotion of type II immunity. There is evidence that tumour-associated macrophages are of the M2 type.

Osteoclasts

Multinucleated cells that mediate bone resorption or osteolysis.

Pulmonary alveolar proteinosis

A rare lung disease in which abnormal accumulation of surfactant occurs, which interferes with gas exchange.

Adjuvant

An agent mixed with an antigen that increases the immune response to that antigen after immunization.

Respiratory burst

A large increase in oxygen consumption and the generation of reactive oxygen species that accompanies the exposure of neutrophils, for example, to microorganisms and/or inflammatory mediators.

Insulin resistance

A condition in which normal amounts of insulin are inadequate to produce a normal insulin response in fat, muscle and liver cells. Various disease states make tissues more resistant to the effects of insulin, such as infection (mediated by TNF).

Felty's syndrome

A condition with the features of rheumatoid arthritis, splenomegaly and granulocytopaenia.

Collagen-induced arthritis

An experimental model of rheumatoid arthritis. The arthritis is induced by immunization of susceptible animals with type II collagen, which is the collagen present in cartilage.

Osteoclastogenesis

A process whereby haematopoietic precursor cells differentiate into osteoclasts.

Microglia

Macrophage-lineage cells that are present in the central nervous system.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of multiple sclerosis. EAE can be induced in several mammalian species by immunization with myelin-derived antigens together with adjuvant.

Glomerulonephritis

An inflammation of the kidney glomeruli that can result in destruction of the glomeruli and renal failure.

MRL–lpr mouse

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in CD95 (also known as FAS), which prevents the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be completely identified.

Chronic obstructive pulmonary disease

(COPD). A group of lung diseases in which airflow is limited and there is airway inflammation and destruction of lung tissue.

Arteriogenesis

The formation of medium-sized blood vessels.

Trophoblast

A cell of the outer layer of the mammalian blastocyst that gives rise to the embryonic portion of the placenta.

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Hamilton, J. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8, 533–544 (2008). https://doi.org/10.1038/nri2356

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