Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gliomas attract brain-resident (microglia) and peripheral macrophages and reprogram these cells into immunosuppressive, pro-invasive cells. M-CSF (macrophage colony-stimulating factor, encoded by the CSF1 gene) has been implicated in the control of recruitment and polarization of macrophages in several cancers. We found that murine GL261 glioma cells overexpress GM-CSF (granulocyte-macrophage colony-stimulating factor encoded by the CSF2 gene) but not M-CSF when compared to normal astrocytes. Knockdown of GM-CSF in GL261 glioma cells strongly reduced microglia-dependent invasion in organotypical brain slices and growth of intracranial gliomas and extended animal survival. The number of infiltrating microglia/macrophages (Iba1(+) cells) and intratumoural angiogenesis were reduced in murine gliomas depleted of GM-CSF. M1/M2 gene profiling in sorted microglia/macrophages suggests impairment of their pro-invasive activation in GM-CSF-depleted gliomas. Deficiency of M-CSF (op/op mice) did not affect glioma growth in vivo and the accumulation of Iba1(+) cells, but impaired accumulation of Iba1(+) cells in response to demyelination. These results suggest that distinct cytokines of the CSF family contribute to macrophage infiltration of tumours and in response to injury. The expression of CSF2 (but not CSF1) was highly up-regulated in glioblastoma patients and we found an inverse correlation between CSF2 expression and patient survival. Therefore we propose that GM-CSF triggers and drives the alternative activation of tumour-infiltrating microglia/macrophages in which these cells support tumour growth and angiogenesis and shape the immune microenvironment of gliomas.
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PMID:Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. 2352 16

Dendritic cells (DCs) are specialized in capture, processing and presentation of antigens to T cells. Depending on the type of DC and its activation state, the interaction of DCs with naive T cells can lead to different types of immune response, or to T-cell tolerance. The existence of many specialized subtypes of DCs with particular functions has raised the need to distinguish DCs formed in steady-state from those produced during an inflammatory response. In patients with autoimmune disease and in experimental animal models of autoimmunity, DCs show abnormalities in both numbers and activation state, expressing immunogenic levels of co-stimulatory molecules and pro-inflammatory cytokines. Initial in vitro studies of cytokines in DC development revealed distinct and important roles for the receptor tyrosine kinases, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF, also called CSF1) and fms-like tyrosine kinase 3 ligand (Flt3L) in the generation of DCs. Flt3L is critical for instructing DC generation throughout different organs and regulates DC development from Flt3(+) lymphoid and myeloid-committed progenitors to DCs in vivo. The aim of this review is to provide an overview of the role of Flt3L-dependent DCs in the immunopathogenesis of autoimmunity and chronic inflammation and its potential as therapeutic targets.
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PMID:Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation. 2411 38

Granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF; also known as CSF1), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) can each play a part in the host response to injury and infection, and there is burgeoning interest in targeting these CSFs in inflammatory and autoimmune disorders, as well as in cancer. For success in clinical medicine, therapeutic targeting will need to be delineated from current strategies. The individual CSFs have unique biological roles, suggesting that they could be used to target specific conditions. This Review compares the CSFs, with a focus on how they could be targeted, discusses the relevant clinical trial data and summarizes the potential clinical applications of targeting each CSF. Importantly, we discuss the novelty of CSF biology and attempt to clarify some of the surrounding misconceptions and issues that can affect therapeutic decisions.
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PMID:Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. 2803 76

Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1Rinh attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.
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PMID:CSF1R signaling is a regulator of pathogenesis in progressive MS. 3309 90

Colony-stimulating factor 1 receptor (CSF1R) inhibitors represent a new class of immune-modulatory drugs, mostly investigated in clinical trials in different malignant neoplasms. Four patients, diagnosed with recurrent or advanced malignant neoplasm and treated with a combination of anti-programmed death ligand 1 and anti-CSF1R monoclonal antibodies, developed an asymptomatic cutaneous eruption characterized by an ill-defined pseudoedematous to waxy diffuse infiltration with a reticular cobblestone-like pattern. Histopathological examination revealed diffuse mucin deposition involving the superficial and mid-dermis with fragmented and scattered elastic fibers. The exact pathogenic mechanisms implicated in the development of mucin deposits in patients treated with CSF1R inhibitors remain to be elucidated. A reduced degradation and clearance of components of the extracellular matrix by macrophages secondary to CSF1 pathway inhibition may be hypothesized. Shredding and fragmentation of elastic fibers may be a result of the increased accumulation of mucopolysaccharides. This observation illustrates the new spectrum of skin-related toxicities secondary to new targeting therapies. This may contribute to a better understanding of the underlying pathogenic mechanisms in skin diseases characterized by a persistent dermal glycosaminoglycan deposition.
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PMID:Diffuse dermal mucinosis secondary to colony-stimulating factor 1 receptor monoclonal antibody treatment: A novel and peculiar drug-induced diffuse cutaneous mucinosis. 3321 89