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Colony-stimulating factors in inflammation and autoimmunity | Nature Reviews Immunology

Nature Reviews Immunology volume 8, pages 533–544 (2008)Cite this article 19k Accesses 1022 Citations 9 Altmetric Metrics details Colony-stimulating factors (CSFs) — granulocyte/macrophage CSF

Nature Reviews Immunology volume 8, pages 533–544 (2008)Cite this article

19k Accesses

1022 Citations

9 Altmetric

Metrics details

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.

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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Burgess, A. W. & Metcalf, D. The nature and action of granulocyte–macrophage colony stimulating factors. Blood 56, 947–958 (1980). This is a seminal early review of CSFs and haematopoiesis.

CAS PubMed Google Scholar

Handman, E. & Burgess, A. W. Stimulation by granulocyte–macrophage colony-stimulating factor of Leishmania tropica killing by macrophages. J. Immunol. 122, 1134–1137 (1979).

CAS PubMed Google Scholar

Hamilton, J. A., Stanley, E. R., Burgess, A. W. & Shadduck, R. K. Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J. Cell. Physiol. 103, 435–445 (1980). This paper was the first to indicate that both GM-CSF and M-CSF could be considered as pro-inflammatory cytokines.

Article CAS PubMed Google Scholar

Whetton, A. D. & Dexter, T. M. Myeloid haemopoietic growth factors. Biochim. Biophys. Acta 989, 111–132 (1989).

CAS PubMed Google Scholar

Hamilton, J. A. Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs. Lancet 342, 536–539 (1993). This hypothesis paper is seminal to many concepts in the Review.

Article CAS PubMed Google Scholar

Verreck, F. A. et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc. Natl Acad. Sci. USA 101, 4560–4565 (2004).

Article CAS PubMed PubMed Central Google Scholar

Fleetwood, A. J., Lawrence, T., Hamilton, J. A. & Cook, A. D. GM-CSF and M-CSF (CSF-1)-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities — implications for CSF blockade in inflammation. J. Immunol. 178, 5245–5252 (2007).

Article CAS PubMed Google Scholar

McKenzie, B. S., Kastelein, R. A. & Cua, D. J. Understanding the IL-23–IL-17 immune pathway. Trends Immunol. 27, 17–23 (2006).

Article CAS PubMed Google Scholar

Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).

Article CAS PubMed Google Scholar

Paniagua, R. T. et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J. Clin. Invest. 116, 2633–2642 (2006).

Article CAS PubMed PubMed Central Google Scholar

Stanley, E. R. et al. Biology and action of colony-stimulating factor-1. Mol. Reprod. Dev. 46, 4–10 (1997).

3.0.CO;2-V" data-track-item_id="10.1002/(SICI)1098-2795(199701)46:13.0.CO;2-V" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291098-2795%28199701%2946%3A1%3C4%3A%3AAID-MRD2%3E3.0.CO%3B2-V" aria-label="Article reference 11" data-doi="10.1002/(SICI)1098-2795(199701)46:13.0.CO;2-V">Article CAS PubMed Google Scholar

Griffin, J. D. et al. The biology of GM-CSF: regulation of production and interaction with its receptor. Int. J. Cell Cloning 8 (Suppl. 1), 35–44 (1990).

Article CAS PubMed Google Scholar

Metcalf, D. Hematopoietic regulators: redundancy or subtlety? Blood 82, 3515–3523 (1993).

CAS PubMed Google Scholar

Hamilton, J. A. GM-CSF in inflammation and autoimmunity. Trends Immunol. 23, 403–408 (2002).

Article CAS PubMed Google Scholar

Hamilton, J. A. & Anderson, G. P. GM-CSF biology. Growth Factors 22, 225–231 (2004).

Article CAS PubMed Google Scholar

Fleetwood, A. J., Cook, A. D. & Hamilton, J. A. Functions of granulocyte–macrophage colony-stimulating factor. Crit. Rev. Immunol. 25, 405–428 (2005).

Article CAS PubMed Google Scholar

Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).

Article CAS PubMed Google Scholar

Metcalf, D. & Nicola, N. A. The Hemopoietic Colony-Stimulating Factors: from Biology to Clinical Applications (University Press, Cambridge, 1995).

Book Google Scholar

Dai, X. M., Zong, X. H., Sylvestre, V. & Stanley, E. R. Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood 103, 1114–1123 (2004).

Article CAS PubMed Google Scholar

Sherr, C. J. et al. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41, 665–676 (1985). This paper defined the M-CSF receptor as the proto-oncogene Fms.

Article CAS PubMed Google Scholar

Pixley, F. J. & Stanley, E. R. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 14, 628–638 (2004).

Article CAS PubMed Google Scholar

Stanley, E. R., Chen, D. M. & Lin, H. S. Induction of macrophage production and proliferation by a purified colony stimulating factor. Nature 274, 168–170 (1978).

Article CAS PubMed Google Scholar

Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

Article CAS PubMed Google Scholar

Hashimoto, S., Suzuki, T., Dong, H. Y., Yamazaki, N. & Matsushima, K. Serial analysis of gene expression in human monocytes and macrophages. Blood 94, 837–844 (1999).

CAS PubMed Google Scholar

Falk, L. A. & Vogel, S. N. Comparison of bone marrow progenitors responsive to granulocyte–macrophage colony stimulating factor and macrophage colony stimulating factor-1. J. Leukocyte Biol. 43, 148–157 (1988).

Article CAS PubMed Google Scholar

Hamilton, J. A. Colony stimulating factors, cytokines and monocyte–macrophages — some controversies. Immunol. Today 14, 18–24 (1993).

Article CAS PubMed Google Scholar

Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002). A review of macrophage polarization.

Article CAS PubMed Google Scholar

Hancock, G. E., Kaplan, G. & Cohn, Z. A. Keratinocyte growth regulation by the products of immune cells. J. Exp. Med. 168, 1395–1402 (1988).

Article CAS PubMed Google Scholar

Herembert, T., Gogusev, J., Zhu, D. L., Drueke, T. B. & Marche, P. Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor. Biochem. J. 325 (Pt 1), 123–128 (1997).

Article CAS PubMed PubMed Central Google Scholar

Soldi, R. et al. Activation of JAK2 in human vascular endothelial cells by granulocyte–macrophage colony-stimulating factor. Blood 89, 863–872 (1997).

CAS PubMed Google Scholar

Ramsay, R. G. et al. Colony-stimulating factor-1 promotes clonogenic growth of normal murine colonic crypt epithelial cells in vitro. J. Interferon Cytokine Res. 24, 416–427 (2004).

Article CAS PubMed Google Scholar

Choi, J. K. et al. Signal transduction pathways of GM-CSF in neural cell lines. Neurosci. Lett. 420, 217–222 (2007).

Article CAS PubMed Google Scholar

Wang, Y., Berezovska, O. & Fedoroff, S. Expression of colony stimulating factor-1 receptor (CSF-1R) by CNS neurons in mice. J. Neurosci. Res. 57, 616–632 (1999).

3.0.CO;2-E" data-track-item_id="10.1002/(SICI)1097-4547(19990901)57:53.0.CO;2-E" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-4547%2819990901%2957%3A5%3C616%3A%3AAID-JNR4%3E3.0.CO%3B2-E" aria-label="Article reference 33" data-doi="10.1002/(SICI)1097-4547(19990901)57:53.0.CO;2-E">Article CAS PubMed Google Scholar

Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl Acad. Sci. USA 87, 4828–4832 (1990). This paper defined the defect in this osteopetrotic mouse as being due to loss of M-CSF function.

Article CAS PubMed PubMed Central Google Scholar

Cecchini, M. G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994).

CAS PubMed Google Scholar

Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994). This report showed, surprisingly at the time, that GM-CSF-deficient mice have relatively normal haematopoiesis with the main phenotype being pulmonary alveolar proteinosis.

Article CAS PubMed PubMed Central Google Scholar

Bezbradica, J. S. et al. Granulocyte–macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny. Immunity 25, 487–497 (2006).

Article CAS PubMed Google Scholar

Antman, K. S. et al. Effect of recombinant human granulocyte–macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N. Engl. J. Med. 319, 593–598 (1988).

Article CAS PubMed Google Scholar

Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Med. 5, 434–438 (1999).

Article CAS PubMed Google Scholar

Shiba, Y. et al. M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1–CXCR4 system. Arterioscler. Thromb. Vasc. Biol. 27, 283–289 (2007).

Article CAS PubMed Google Scholar

Armitage, J. O. Emerging applications of recombinant human granulocyte–macrophage colony-stimulating factor. Blood 92, 4491–4508 (1998).

CAS PubMed Google Scholar

Shortman, K. & Naik, S. H. Steady-state and inflammatory dendritic-cell development. Nature Rev. Immunol. 7, 19–30 (2007).

Article CAS Google Scholar

Menetrier-Caux, C. et al. Inhibition of the differentiation of dendritic cells from CD34+ progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92, 4778–4791 (1998).

CAS PubMed Google Scholar

Willman, C. L., Stewart, C. C., Miller, V., Yi, T. L. & Tomasi, T. B. Regulation of MHC class II gene expression in macrophages by hematopoietic colony-stimulating factors (CSF). Induction by granulocyte/macrophage CSF and inhibition by CSF-1. J. Exp. Med. 170, 1559–1567 (1989).

Article CAS PubMed Google Scholar

Phillips, W. A. & Hamilton, J. A. Colony stimulating factor-1 is a negative regulator of the macrophage respiratory burst. J. Cell. Physiol. 144, 190–196 (1990).

Article CAS PubMed Google Scholar

Lari, R. et al. Macrophage lineage phenotypes and osteoclastogenesis — complexity in the control by GM-CSF and TGF-β. Bone 40, 323–336 (2007).

Article CAS PubMed Google Scholar

De, A. K., Laudanski, K. & Miller-Graziano, C. L. Failure of monocytes of trauma patients to convert to immature dendritic cells is related to preferential macrophage-colony-stimulating factor-driven macrophage differentiation. J. Immunol. 170, 6355–6362 (2003).

Article CAS PubMed Google Scholar

Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

Article CAS PubMed Google Scholar

Guidez, F., Li, A. C., Horvai, A., Welch, J. S. & Glass, C. K. Differential utilization of Ras signaling pathways by macrophage colony-stimulating factor (CSF) and granulocyte–macrophage CSF receptors during macrophage differentiation. Mol. Cell Biol. 18, 3851–3861 (1998).

Article CAS PubMed PubMed Central Google Scholar

Firestein, G. S. & Zvaifler, N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768–773 (1990).

Article CAS PubMed Google Scholar

Hamilton, J. A., Campbell, I. K., Wojta, J. & Cheung, D. Plasminogen activators and their inhibitors in arthritic disease. Ann. NY Acad. Sci. 667, 87–100 (1992).

Article CAS PubMed Google Scholar

Bresnihan, B. et al. Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: standardization and consistency across centers. J. Rheumatol. 34, 620–622 (2007).

PubMed Google Scholar

Leizer, T., Cebon, J., Layton, J. E. & Hamilton, J. A. Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. Blood 76, 1989–1996 (1990).

CAS PubMed Google Scholar

Hamilton, J. A., Filonzi, E. L. & Ianches, G. Regulation of macrophage colony-stimulating factor (M-CSF) production in cultured human synovial fibroblasts. Growth Factors 9, 157–165 (1993).

Article CAS PubMed Google Scholar

Campbell, I. K., Novak, U., Cebon, J., Layton, J. E. & Hamilton, J. A. Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J. Immunol. 147, 1238–1246 (1991).

CAS PubMed Google Scholar

Campbell, I. K., Ianches, G. & Hamilton, J. A. Production of macrophage colony-stimulating factor (M-CSF) by human articular cartilage and chondrocytes. Modulation by interleukin-1 and tumor necrosis factor-α. Biochim. Biophys. Acta 1182, 57–63 (1993).

Article CAS PubMed Google Scholar

Nakano, K. et al. Rheumatoid synovial endothelial cells produce macrophage colony-stimulating factor leading to osteoclastogenesis in rheumatoid arthritis. Rheumatology (Oxford) 46, 597–603 (2007).

Article CAS Google Scholar

Niki, Y. et al. Administration of cyclooxygenase-2 inhibitor reduces joint inflammation but exacerbates osteopenia in IL-1α transgenic mice due to GM-CSF overproduction. J. Immunol. 179, 639–646 (2007).

Article CAS PubMed Google Scholar

Campbell, I. K., Bendele, A., Smith, D. A. & Hamilton, J. A. Granulocyte–macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Ann. Rheum. Dis. 56, 364–368 (1997).

Article CAS PubMed PubMed Central Google Scholar

Bischof, R. J., Zafiropoulos, D., Hamilton, J. A. & Campbell, I. K. Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation. Clin. Exp. Immunol. 119, 361–367 (2000).

Article CAS PubMed PubMed Central Google Scholar

Abd, A. H., Savage, N. W., Halliday, W. J. & Hume, D. A. The role of macrophages in experimental arthritis induced by Streptococcus agalactiae sonicate: actions of macrophage colony-stimulating factor (CSF-1) and other macrophage-modulating agents. Lymphokine Cytokine Res. 10, 43–50 (1991).

CAS PubMed Google Scholar

Campbell, I. K., Rich, M. J., Bischof, R. J. & Hamilton, J. A. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J. Leukocyte Biol. 68, 144–150 (2000). This was the first paper to show that neutralization of M-CSF suppressed an inflammatory and autoimmune disease.

CAS PubMed Google Scholar

Hazenberg, B. P., Van Leeuwen, M. A., Van Rijswijk, M. H., Stern, A. C. & Vellenga, E. Correction of granulocytopenia in Felty's syndrome by granulocyte–macrophage colony-stimulating factor. Simultaneous induction of interleukin-6 release and flare-up of the arthritis. Blood 74, 2769–2770 (1989).

CAS PubMed Google Scholar

Campbell, I. K. et al. Protection from collagen-induced arthritis in granulocyte–macrophage colony-stimulating factor-deficient mice. J. Immunol. 161, 3639–3644 (1998). This paper showed for the first time that collagen-induced arthritis could be induced significantly in C57BL/6 mice, enabling the authors to show that GM-CSF-deficient mice had almost no disease.

CAS PubMed Google Scholar

Cook, A. D., Braine, E. L., Campbell, I. K., Rich, M. J. & Hamilton, J. A. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 3, 293–298 (2001).

Article CAS PubMed PubMed Central Google Scholar

Ohno, H. et al. The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model. Eur. J. Immunol. 38, 283–291 (2008).

Article CAS PubMed Google Scholar

Ando, W. et al. Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA). J. Bone Miner. Metab. 24, 274–282 (2006).

Article CAS PubMed Google Scholar

Kitaura, H. et al. M-CSF mediates TNF-induced inflammatory osteolysis. J. Clin. Invest. 115, 3418–3427 (2005).

Article CAS PubMed PubMed Central Google Scholar

Yang, Y. H. & Hamilton, J. A. Dependence of interleukin-1-induced arthritis on granulocyte–macrophage colony-stimulating factor. Arthritis Rheum. 44, 111–119 (2001).

3.0.CO;2-1" data-track-item_id="10.1002/1529-0131(200101)44:13.0.CO;2-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F1529-0131%28200101%2944%3A1%3C111%3A%3AAID-ANR15%3E3.0.CO%3B2-1" aria-label="Article reference 69" data-doi="10.1002/1529-0131(200101)44:13.0.CO;2-1">Article PubMed Google Scholar

Plater-Zyberk, C. et al. GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice. Ann. Rheum. Dis. 66, 452–457 (2007).

Article CAS PubMed Google Scholar

Lawlor, K. E., Wong, P. K., Campbell, I. K., van Rooijen, N. & Wicks, I. P. Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte–macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor. Arthritis Rheum. 52, 3749–3754 (2005).

Article CAS PubMed Google Scholar

Yao, Z. et al. Tumor necrosis factor-α increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J. Biol. Chem. 281, 11846–11855 (2006).

Article CAS PubMed Google Scholar

McQualter, J. L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001).

Article CAS PubMed PubMed Central Google Scholar

Fischer, H. G., Bielinsky, A. K., Nitzgen, B., Daubener, W. & Hadding, U. Functional dichotomy of mouse microglia developed in vitro: differential effects of macrophage and granulocyte/macrophage colony-stimulating factor on cytokine secretion and antitoxoplasmic activity. J. Neuroimmunol. 45, 193–201 (1993).

Article CAS PubMed Google Scholar

Marusic, S. et al. Local delivery of granulocyte macrophage colony-stimulating factor by retrovirally transduced antigen-specific T cells leads to severe, chronic experimental autoimmune encephalomyelitis in mice. Neurosci. Lett. 332, 185–189 (2002).

Article CAS PubMed Google Scholar

Ponomarev, E. D. et al. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178, 39–48 (2007).

Article CAS PubMed Google Scholar

Schneider, U. C. et al. Granulocyte–macrophage colony-stimulating factor-induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion. Stroke 38, 1320–1328 (2007).

Article CAS PubMed Google Scholar

Hao, A. J., Dheen, S. T. & Ling, E. A. Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage. Neuroscience 112, 889–900 (2002).

Article CAS PubMed Google Scholar

Vincent, V. A., Robinson, C. C., Simsek, D. & Murphy, G. M. Macrophage colony stimulating factor prevents NMDA-induced neuronal death in hippocampal organotypic cultures. J. Neurochem. 82, 1388–1397 (2002).

Article CAS PubMed Google Scholar

Kitching, A. R. et al. The requirement for granulocyte–macrophage colony-stimulating factor and granulocyte colony-stimulating factor in leukocyte-mediated immune glomerular injury. J. Am. Soc. Nephrol. 13, 350–358 (2002).

CAS PubMed Google Scholar

Timoshanko, J. R., Kitching, A. R., Semple, T. J., Holdsworth, S. R. & Tipping, P. G. Granulocyte macrophage colony-stimulating factor expression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis. J. Am. Soc. Nephrol. 16, 2646–2656 (2005).

Article CAS PubMed Google Scholar

Lenda, D. M., Kikawada, E., Stanley, E. R. & Kelley, V. R. Reduced macrophage recruitment, proliferation, and activation in colony-stimulating factor-1-deficient mice results in decreased tubular apoptosis during renal inflammation. J. Immunol. 170, 3254–3262 (2003).

Article CAS PubMed Google Scholar

Le Meur, Y. et al. Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-Fms pathway. J. Leukocyte Biol. 72, 530–537 (2002).

CAS PubMed Google Scholar

Bozinovski, S., Jones, J. E., Vlahos, R., Hamilton, J. A. & Anderson, G. P. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFκB and AP-1 in vivo. J. Biol. Chem. 277, 42808–42814 (2002).

Article CAS PubMed Google Scholar

Bozinovski, S. et al. Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L877–L885 (2004).

Article CAS PubMed Google Scholar

Cates, E. C. et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J. Immunol. 173, 6384–6392 (2004).

Article CAS PubMed Google Scholar

Vlahos, R., Bozinovski, S., Hamilton, J. A. & Anderson, G. P. Therapeutic potential of treating chronic obstructive pulmonary disease (COPD) by neutralising granulocyte macrophage colony-stimulating factor (GM-CSF). Pharmacol. Ther. 112, 106–115 (2006).

Article CAS PubMed Google Scholar

Yamashita, N. et al. Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF). Cell. Immunol. 219, 92–97 (2002).

Article CAS PubMed Google Scholar

Su, Y. C., Rolph, M. S., Hansbro, N. G., Mackay, C. R. & Sewell, W. A. Granulocyte–macrophage colony-stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation. J. Immunol. 180, 2600–2607 (2008).

Article CAS PubMed Google Scholar

Ishikawa, T., Aoshiba, K., Yokohori, N. & Nagai, A. Macrophage colony-stimulating factor aggravates rather than regenerates emphysematous lungs in mice. Respiration 73, 538–545 (2006).

Article CAS PubMed Google Scholar

Baran, C. P. et al. Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 176, 78–89 (2007).

Article CAS PubMed PubMed Central Google Scholar

Haghighat, A., Weiss, D., Whalin, M. K., Cowan, D. P. & Taylor, W. R. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation 115, 2049–2054 (2007).

Article CAS PubMed Google Scholar

Ditiatkovski, M., Toh, B. H. & Bobik, A. GM-CSF deficiency reduces macrophage PPAR-γ expression and aggravates atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 2337–2344 (2006).

Article CAS PubMed Google Scholar

Shindo, J. et al. Granulocyte–macrophage colony-stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits. Circulation 99, 2150–2156 (1999).

Article CAS PubMed Google Scholar

Shaposhnik, Z., Wang, X., Weinstein, M., Bennett, B. J. & Lusis, A. J. Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 27, 621–627 (2007).

Article CAS PubMed Google Scholar

Bergmann, C. E. et al. Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice. J. Leukocyte Biol. 80, 59–65 (2006).

Article CAS PubMed Google Scholar

Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004). This review summarizes the role of M-CSF and tumour-associated macrophages in promoting tumour progression and metastasis.

Article CAS Google Scholar

Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

Article CAS PubMed Google Scholar

Lamagna, C., Aurrand-Lions, M. & Imhof, B. A. Dual role of macrophages in tumor growth and angiogenesis. J. Leukocyte Biol. 80, 705–713 (2006).

Article CAS PubMed Google Scholar

Young, M. R. et al. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int. J. Cancer 67, 333–338 (1996).

3.0.CO;2-S" data-track-item_id="10.1002/(SICI)1097-0215(19960729)67:33.0.CO;2-S" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-0215%2819960729%2967%3A3%3C333%3A%3AAID-IJC5%3E3.0.CO%3B2-S" aria-label="Article reference 100" data-doi="10.1002/(SICI)1097-0215(19960729)67:33.0.CO;2-S">Article CAS PubMed Google Scholar

Takeda, K., Hatakeyama, K., Tsuchiya, Y., Rikiishi, H. & Kumagai, K. A correlation between GM-CSF gene expression and metastases in murine tumors. Int. J. Cancer 47, 413–420 (1991).

Article CAS PubMed Google Scholar

Park, B. K. et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nature Med. 13, 62–69 (2007).

Article CAS PubMed Google Scholar

Paulus, P., Stanley, E. R., Schafer, R., Abraham, D. & Aharinejad, S. Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res. 66, 4349–4356 (2006).

Article CAS PubMed Google Scholar

Ohno, H. et al. A c-Fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol. Cancer Ther. 5, 2634–2643 (2006).

Article CAS PubMed Google Scholar

Reed, J. A. et al. GM-CSF action in the CNS decreases food intake and body weight. J. Clin. Invest. 115, 3035–3044 (2005).

Article CAS PubMed PubMed Central Google Scholar

Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

Article CAS PubMed PubMed Central Google Scholar

Levine, J. A., Jensen, M. D., Eberhardt, N. L. & O'Brien, T. Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth. J. Clin. Invest. 101, 1557–1564 (1998).

Article CAS PubMed PubMed Central Google Scholar

Wei, S. et al. Modulation of CSF-1-regulated post-natal development with anti-CSF-1 antibody. Immunobiology 210, 109–119 (2005).

Article CAS PubMed Google Scholar

Gaudreau, S. et al. Granulocyte–macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells. J. Immunol. 179, 3638–3647 (2007).

Article CAS PubMed Google Scholar

Watanabe, Y. et al. Effect of macrophage colony-stimulating factor on the development of diabetes mellitus in BB rats. Horm. Metab. Res. 25, 323–324 (1993).

Article CAS PubMed Google Scholar

Schon, M., Denzer, D., Kubitza, R. C., Ruzicka, T. & Schon, M. P. Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice. J. Invest. Dermatol. 114, 976–983 (2000).

Article CAS PubMed Google Scholar

Keller, M. et al. T cell-regulated neutrophilic inflammation in autoinflammatory diseases. J. Immunol. 175, 7678–7686 (2005).

Article CAS PubMed Google Scholar

Kaplan, G. et al. Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing. J. Exp. Med. 175, 1717–1728 (1992).

Article CAS PubMed Google Scholar

Wu, L., Yu, Y. L., Galiano, R. D., Roth, S. I. & Mustoe, T. A. Macrophage colony-stimulating factor accelerates wound healing and upregulates TGF-β1 mRNA levels through tissue macrophages. J. Surg. Res. 72, 162–169 (1997).

Article CAS PubMed Google Scholar

Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265–273 (2006).

Article CAS Google Scholar

Korzenik, J. R., Dieckgraefe, B. K., Valentine, J. F., Hausman, D. F. & Gilbert, M. J. Sargramostim for active Crohn's disease. N. Engl. J. Med. 352, 2193–2201 (2005).

Article CAS PubMed Google Scholar

Sainathan, S. K. et al. Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis. Inflamm. Bowel Dis. 14, 88–99 (2008).

Article PubMed Google Scholar

Marshall, D., Cameron, J., Lightwood, D. & Lawson, A. D. Blockade of colony stimulating factor-1 (CSF-I) leads to inhibition of DSS-induced colitis. Inflamm. Bowel Dis. 13, 219–224 (2007).

Article PubMed Google Scholar

Ghia, J. E. et al. Role of M-CSF dependent macrophages in colitis is driven by the nature of the inflammatory stimulus. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G770–G777 (2008).

Article CAS PubMed Google Scholar

Sweet, M. J. & Hume, D. A. CSF-1 as a regulator of macrophage activation and immune responses. Arch. Immunol. Ther. Exp. (Warsz) 51, 169–177 (2003).

CAS Google Scholar

McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rev. Immunol. 7, 429–442 (2007).

Article CAS Google Scholar

Haworth, C. et al. Expression of granulocyte–macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-α. Eur. J. Immunol. 21, 2575–2579 (1991).

Article CAS PubMed Google Scholar

Niki, Y. et al. Macrophage- and neutrophil-dominant arthritis in human IL-1α transgenic mice. J. Clin. Invest. 107, 1127–1135 (2001).

Article CAS PubMed PubMed Central Google Scholar

Campbell, I. K., O'Donnell, K., Lawlor, K. E. & Wicks, I. P. Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J. Clin. Invest. 107, 1519–1527 (2001).

Article CAS PubMed PubMed Central Google Scholar

Cook, A. D., Braine, E. L. & Hamilton, J. A. Stimulus-dependent requirement for granulocyte–macrophage colony-stimulating factor in inflammation. J. Immunol. 173, 4643–4651 (2004).

Article CAS PubMed Google Scholar

Conway, J. G. et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc. Natl Acad. Sci. USA 102, 16078–16083 (2005).

Article CAS PubMed PubMed Central Google Scholar

Seymour, J. F. Extra-pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte–macrophage colony-stimulating factor-deficient mice. Respirology 11, S16–S22 (2006).

Article PubMed Google Scholar

Robertson, S. A. GM-CSF regulation of embryo development and pregnancy. Cytokine Growth Factor Rev. 18, 287–298 (2007).

Article CAS PubMed Google Scholar

Roberts, A. W. G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 23, 33–41 (2005).

Article CAS PubMed Google Scholar

Lieschke, G. J. et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84, 1737–1746 (1994).

CAS PubMed Google Scholar

Lawlor, K. E. et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc. Natl Acad. Sci. USA 101, 11398–11403 (2004). This paper provides evidence of a role for G-CSF in models of arthritis.

Article CAS PubMed PubMed Central Google Scholar

Solaroglu, I., Jadhav, V. & Zhang, J. H. Neuroprotective effect of granulocyte-colony stimulating factor. Front. Biosci. 12, 712–724 (2007).

Article CAS PubMed Google Scholar

Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

Article CAS PubMed Google Scholar

Kawanaka, N. et al. CD14+, CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum. 46, 2578–2586 (2002).

Article CAS PubMed Google Scholar

Chapoval, A. I., Kamdar, S. J., Kremlev, S. G. & Evans, R. CSF-1 (M-CSF) differentially sensitizes mononuclear phagocyte subpopulations to endotoxin in vivo: a potential pathway that regulates the severity of Gram-negative infections. J. Leukocyte Biol. 63, 245–252 (1998).

Article CAS PubMed Google Scholar

Bruhns, P., Samuelsson, A., Pollard, J. W. & Ravetch, J. V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18, 573–581 (2003).

Article CAS PubMed Google Scholar

Guan, Y. et al. Antigen presenting cells treated in vitro by macrophage colony-stimulating factor and autoantigen protect mice from autoimmunity. J. Neuroimmunol. 192, 68–78 (2007).

Article CAS PubMed PubMed Central Google Scholar

Hamilton, J. A. et al. Oxidized LDL can induce macrophage survival, DNA synthesis, and enhanced proliferative response to CSF-1 and GM-CSF. Arterioscler. Thromb. Vasc. Biol. 19, 98–105 (1999).

Article CAS PubMed Google Scholar

Lin, H. et al. Regulation of myeloid growth and differentiation by a novel cytokine, interleukin-34 (IL-34), via the CSF-1 receptor. Cytokine 39, 24 (2007).

Article Google Scholar

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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.

Department of Medicine, Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, The Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia

John A. Hamilton

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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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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).

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.

Multinucleated cells that mediate bone resorption or osteolysis.

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

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

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.

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).

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

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.

A process whereby haematopoietic precursor cells differentiate into osteoclasts.

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

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

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

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.

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

The formation of medium-sized blood vessels.

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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Issue Date: July 2008

DOI: https://doi.org/10.1038/nri2356

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