Colony-stimulating factor in inflammation and autoimmunity

Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, Department of Medicine, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
Nature Reviews Immunology (Impact Factor: 34.99). 08/2008; 8(7):533-44. DOI: 10.1038/nri2356
Source: PubMed


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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    • "CSF1R expression has been reported on immunosuppressive myeloid cells and dendritic cells [41] [42] [43]. CSF1-CSF1R signaling regulates survival, differentiation, and proliferation of monocytes and macrophages [44] [45], and have critical role in angiogenesis and tumor progression [46] [47]. Therefore, the goals of the present study are to (1) investigate the effect of CSF1R blockade on orthotopic glioma development in a recently established preclinical chimeric mouse model, (2) to evaluate whether CSF1R blockade alone or in combination with VEGFR2 blockade could inhibit the homing of myeloid BMDCs to the glioma, (3) to identify signature immune cell populations following CSF1R inhibition that could have profound role in glioma growth and (4) to investigate key secreted molecular signatures in GBM TME following CSF1R inhibition. "
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    ABSTRACT: Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 10(6) GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade.
    Cancer letters 09/2015; 369(2). DOI:10.1016/j.canlet.2015.09.004 · 5.62 Impact Factor
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    • "Caescu et al. [50] showed that treatment of macrophages with CSF1 upregulates miR-21 resulting in a robust anti-inflammatory effect which favors M2 differentiation [50]. This is in agreement with the concept of CSF1 receptor signaling being essential for M2 differentiation and inhibition of the M1 phenotype [51]. Wang et al. [52] found that in thioglycollate-elicited peritoneal macrophages miR-21 is downregulated by activation of a prostaglandin E 2 (PGE 2 )/cyclic AMP pathway which results in enhanced expression of M2-but not M1-related genes. "
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    ABSTRACT: Efforts in experimental therapeutics of atherosclerosis are mostly focused on identifying candidate targets that can be exploited in developing new strategies to reduce plaque progression, induce its regression and/or improve stability of advanced lesions. Plaque macrophages are central players in all these processes, and consequently a significant amount of research is devoted to understanding mechanisms that regulate, for instance, macrophage apoptosis, necrosis or migration. Macrophage diversity is a key feature of the macrophage population in the plaque and can impact many aspects of lesion development. Thus, searching for molecular entities that contribute to atherorelevant functions of a specific macrophage type but not others may lead to identification of targets that can be exploited in phenotype selective modulation of the lesional macrophage. This however, remains an unmet goal. In recent years several studies have revealed critical functions of micro-RNAs (miRs) in mechanisms of macrophage polarization, and a number of miRs have emerged as being specific of distinctive macrophage subsets. Not only can these miRs represent the first step towards recognition of phenotype specific targets, but they may also pave the way to reveal novel atherorelevant pathways within macrophage subsets. This article discusses some of these recent findings, speculates on their potential relevance to atherosclerosis and elaborates on the prospective use of miRs to affect the function of plaque macrophages in a phenotype selective manner.
    08/2015; 3:BBREPD1500144. DOI:10.1016/j.bbrep.2015.08.009
    • "Interestingly, evidence from knock-out (KO) mouse studies suggest that the steady state maintenance of myeloid lineage cells depend more critically on G-CSF, M-CSF and Fms like tyrosine kinase-3 ligand (Flt3L) while GM-CSF is largely dispensable for this purpose [1]. GM-CSF KO mice do not show any abnormalities in the steady state myelopoiesis (including no change in peripheral monocyte numbers) except for a small reduction in dendritic cell numbers [24] [25] [26] [27]. However, GM-CSF is able to modulate myeloid lineage populations in specialized ways. "
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    ABSTRACT: GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune-modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases such as Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune-modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine 06/2015; 75(2). DOI:10.1016/j.cyto.2015.05.030 · 2.66 Impact Factor
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