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Colony stimulating factors in the nervous system.

ABSTRACT: Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.

SUBMITTER: Chitu V

PROVIDER: S-EPMC8671346 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Colony stimulating factors in the nervous system.

Chitu Violeta V Biundo Fabrizio F Stanley E Richard ER

Seminars in immunology 20210401

Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1 ...[more]

PMID: 34743926

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pH responsive granulocyte colony-stimulating factor variants with implications for treating Alzheimer's disease and other central nervous system disorders.

Project description:Systemic injection of granulocyte colony-stimulating factor (G-CSF) has yielded encouraging results in treating Alzheimer's Disease (AD) and other central nervous system (CNS) disorders. Making G-CSF a viable AD therapeutic will, however, require increasing G-CSF's ability to stimulate neurons within the brain. This objective could be realized by increasing transcytosis of G-CSF across the blood brain barrier (BBB). An established correlation between G-CSF receptor (G-CSFR) binding pH responsiveness and increased recycling of G-CSF to the cell exterior after endocytosis motivated development of G-CSF variants with highly pH responsive G-CSFR binding affinities. These variants will be used in future validation of our hypothesis that increased BBB transcytosis can enhance G-CSF therapeutic efficacy. Flow cytometric screening of a yeast-displayed library in which G-CSF/G-CSFR interface residues were mutated to histidine yielded a G-CSF triple His mutant (L109H/D110H/Q120H) with highly pH responsive binding affinity. This variant's KD, measured by surface plasmon resonance (SPR), increases ∼20-fold as pH decreases from 7.4 to below histidine's pKa of ∼6.0; an increase 2-fold greater than for previously reported G-CSF His mutants. Cell-free protein synthesis (CFPS) enabled expression and purification of soluble, bioactive G-CSF triple His variant protein, an outcome inaccessible via Escherichia coli inclusion body refolding. This purification and bioactivity validation will enable future identification of correlations between pH responsiveness and transcytosis in BBB cell culture model and animal experiments. Furthermore, the library screening and CFPS methods employed here could be applied to developing other pH responsive hematopoietic or neurotrophic factors for treating CNS disorders.

| S-EPMC4596278 | biostudies-literature

The receptor for granulocyte-colony stimulating factor (G-CSF) is expressed in radial glia during development of the nervous system.

Project description:BackgroundGranulocyte colony-stimulating (G-CSF) factor is a well-known hematopoietic growth factor stimulating the proliferation and differentiation of myeloid progenitors. Recently, we uncovered that G-CSF acts also as a neuronal growth factor in the brain, which promotes adult neural precursor differentiation and enhances regeneration of the brain after insults. In adults, the receptor for G-CSF is predominantly expressed in neurons in many brain areas. We also described expression in neurogenic regions of the adult brain, such as the subventricular zone and the subgranular layer of the dentate gyrus. In addition, we found close co-localization of the G-CSF receptor and its ligand G-CSF. Here we have conducted a systematic expression analysis of G-CSF receptor and its ligand in the developing embryo.ResultsOutside the central nervous system (CNS) we found G-CSF receptor expression in blood vessels, muscles and their respective precursors and neurons. The expression of the G-CSF receptor in the developing CNS was most prominent in radial glia cells.ConclusionOur data imply that in addition to the function of G-CSF and its receptor in adult neurogenesis, this system also has a role in embryonic neurogenesis and nervous system development.

| S-EPMC2329616 | biostudies-literature

Differential regulation of microglial states by colony stimulating factors.

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Genomic analysis of the prognostic value of colony-stimulating factors (CSFs) and colony-stimulating factor receptors (CSFRs) across 24 solid cancer types.

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| S-EPMC7475477 | biostudies-literature

Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system.

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| S-EPMC6996135 | biostudies-literature

Structural Analysis of the Colony-Stimulating Factor 3 Gene of Granulocyte Colony-Stimulating Factor-Producing Urothelial Cancer.

Project description:Background Granulocyte colony-stimulating factor (G-CSF) is a member of the CSF family of glycoproteins that regulate the proliferation, differentiation, and mobilization of neutrophils. G-CSF-producing malignant cancers have been reported to occur in various organs and are mostly associated with poor clinical prognosis. Here, we analyzed the structure of the CSF3 gene encoding the G-CSF protein to delineate the mechanism of G-CSF production by the cancer cells. Methodology Two cases of G-CSF-producing urothelial cancers and three cases of G-CSF-nonproducing bladder cancers were enrolled for genetic analysis. Results In one case of G-CSF-producing bladder cancer, six somatic mutations were detected in the 5'- upstream region of the CSF3 gene. No somatic mutations in the CSF3 gene were detected in another case of G-CSF-producing renal pelvic cancer and G-CSF-nonproducing bladder cancers. Copy numbers of the CSF3 gene were not increased in G-CSF-producing urothelial cancers. Conclusions Somatic mutations in the 5'- upstream region of the CSF3 gene may cause G-CSF protein overproduction.

| S-EPMC10516146 | biostudies-literature

Granulocyte and granulocyte-macrophage colony stimulating factors for newly diagnosed patients with myelodysplastic syndromes.

Project description: Not available

| S-EPMC10405220 | biostudies-literature

A Survey of Oncologists' Perceptions and Opinions Regarding the Use of Granulocyte Colony-Stimulating Factors.

Project description:The purpose of the study is to describe oncologists' perceptions and opinions about patient eligibility, guidelines, and barriers for use of granulocyte colony-stimulating factor (G-CSF), overall and stratified by their affiliation with the Oncology Care Model (OCM). In May 2018, we invited and recruited practicing US oncologists from a national database for an online survey. Level of agreement was identified using a seven-point scale, ranging from strongly disagree to strongly agree. Of 200 participating oncologists, 70 were OCM-affiliated. Overall, 65% of oncologists agreed or strongly agreed that all patients at high risk of febrile neutropenia (FN) should receive prophylactic G-CSF, and half agreed or strongly agreed that benefits of G-CSF outweigh the potential adverse effects. The most common barriers to G-CSF use for patients at high risk of FN included patient refusal (37.1% of OCM-affiliated oncologists vs. 21.5% of non-OCM-affiliated oncologists), not on protocol/not supported by guidelines (32.9% vs. 23.1%), lack of reimbursement to practice (30.0% vs. 15.4%), and concerns about insurance coverage (22.9% vs. 26.9%). More OCM-affiliated oncologists reported that their practices offer and strongly encourage adherence to a specific protocol for G-CSF use (49.2%) versus non-OCM oncologists (31.3%). Despite recommendations from national guidelines and strong evidence from randomized, controlled clinical trials, only two thirds of oncologists agree or strongly agree that all patients at high risk of FN should receive primary G-CSF prophylaxis. Decisions about G-CSF prophylaxis may be affected by factors other than risk of FN, such as patient choice, practice protocols/guidelines, lack of reimbursement, and insurance coverage.

| S-EPMC6971139 | biostudies-literature

Transcriptional mechanisms underlying sensitization of peripheral sensory neurons by granulocyte-/granulocyte-macrophage colony stimulating factors.

Project description:BackgroundCancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth factors, namely granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF), are abundantly released in the tumor microenvironment and play a key role in regulating tumor-nerve interactions and tumor-associated pain by activating receptors on dorsal root ganglion (DRG) neurons. Moreover, these hematopoietic factors have been highly implicated in postsurgical pain, inflammatory pain and osteoarthritic pain. However, the molecular mechanisms via which G-/GMCSF bring about nociceptive sensitization and elicit pain are not known.ResultsIn order to elucidate G-/GMCSF mediated transcriptional changes in the sensory neurons, we performed a comprehensive, genome-wide analysis of changes in the transcriptome of DRG neurons brought about by exposure to GMCSF or GCSF. We present complete information on regulated genes and validated profiling analyses and report novel regulatory networks and interaction maps revealed by detailed bioinformatics analyses. Amongst these, we validate calpain 2, matrix metalloproteinase 9 (MMP9) and a RhoGTPase Rac1 as well as Tumor necrosis factor alpha (TNF?) as transcriptional targets of G-/GMCSF and demonstrate the importance of MMP9 and Rac1 in GMCSF-induced nociceptor sensitization.ConclusionWith integrative approach of bioinformatics, in vivo pharmacology and behavioral analyses, our results not only indicate that transcriptional control by G-/GMCSF signaling regulates a variety of established pain modulators, but also uncover a large number of novel targets, paving the way for translational analyses in the context of pain disorders.

| S-EPMC3852053 | biostudies-literature

Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors.

Project description:In atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

| S-EPMC7921113 | biostudies-literature

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