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Csf1 microglia

Nunzia Pastore, Owen A Brady, Heba I Diab, José A Martina, Lu Sun, Tuong Huynh, Jeong-A Lim, Hossein Zare, Nina Raben, Andrea Ballabio, Rosa Puertollano
The activation of transcription factors is critical to ensure an effective defense against pathogens. In this study we identify a critical and complementary role of the transcription factors TFEB and TFE3 in innate immune response. By using a combination of chromatin immunoprecipitation, CRISPR-Cas9-mediated genome-editing technology, and in vivo models, we determined that TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines...
August 2, 2016: Autophagy
Ishani De, Megan D Steffen, Paul A Clark, Clayton J Patros, Emily Sokn, Stephanie M Bishop, Suzanne Litscher, Vilena I Maklakova, John S Kuo, Fausto J Rodriguez, Lara S Collier
Current therapies for high-grade gliomas extend survival only modestly. The glioma microenvironment, including glioma-associated microglia/macrophages (GAM), is a potential therapeutic target. The microglia/macrophage cytokine CSF1 and its receptor CSF1R are overexpressed in human high-grade gliomas. To determine whether the other known CSF1R ligand IL34 is expressed in gliomas, we examined expression array data of human high-grade gliomas and performed RT-PCR on glioblastoma sphere-forming cell lines (GSC)...
May 1, 2016: Cancer Research
Zhonghui Guan, Julia A Kuhn, Xidao Wang, Bradley Colquitt, Carlos Solorzano, Smitha Vaman, Andrew K Guan, Zoe Evans-Reinsch, Joao Braz, Marshall Devor, Sherry L Abboud-Werner, Lewis L Lanier, Stavros Lomvardas, Allan I Basbaum
Although microglia have been implicated in nerve injury-induced neuropathic pain, the manner by which injured sensory neurons engage microglia remains unclear. We found that peripheral nerve injury induced de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. CSF1 was transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglial activation and proliferation...
January 2016: Nature Neuroscience
Nicholas Butowski, Howard Colman, John F De Groot, Antonio M Omuro, Lakshmi Nayak, Patrick Y Wen, Timothy F Cloughesy, Adhirai Marimuthu, Sam Haidar, Arie Perry, Jason Huse, Joanna Phillips, Brian L West, Keith B Nolop, Henry H Hsu, Keith L Ligon, Annette M Molinaro, Michael Prados
BACKGROUND: The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development...
April 2016: Neuro-oncology
Shankar Sadasivan, Mark Zanin, Kevin O'Brien, Stacey Schultz-Cherry, Richard J Smeyne
Although influenza is primarily a respiratory disease, it has been shown, in some cases, to induce encephalitis, including people acutely infected with the pandemic A/California/04/2009 (CA/09) H1N1 virus. Based on previous studies showing that the highly pathogenic avian influenza (HPAI) A/Vietnam/1203/2004 H5N1 virus was neurotropic, induced CNS inflammation and a transient parkinsonism, we examined the neurotropic and inflammatory potential of the CA/09 H1N1 virus in mice. Following intranasal inoculation, we found no evidence for CA/09 H1N1 virus neurotropism in the enteric, peripheral or central nervous systems...
2015: PloS One
Jun-Ichi Satoh, Naohiro Asahina, Shouta Kitano, Yoshihiro Kino
Microglia are resident mononuclear phagocytes that play a principal role in the maintenance of normal tissue homeostasis in the central nervous system (CNS). Microglia, rapidly activated in response to proinflammatory stimuli, are accumulated in brain lesions of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The E26 transformation-specific (ETS) family transcription factor PU.1/Spi1 acts as a master regulator of myeloid and lymphoid development. PU.1-deficient mice show a complete loss of microglia, indicating that PU...
2014: Gene Regulation and Systems Biology
Maureen Karrer, Martin Alexander Lopez, Daniel Meier, Cyril Mikhail, Omolara O Ogunshola, Andreas Felix Müller, Laura Strauss, Mehdi Tafti, Adriano Fontana
Interactions of neurons with microglia may play a dominant role in sleep regulation. TNF may exert its somnogeneic effects by promoting attraction of microglia and their processes to the vicinity of dendrites and synapses. We found TNF to stimulate neurons (i) to produce CCL2, CCL7 and CXCL10, chemokines acting on mononuclear phagocytes and (ii) to stimulate the expression of the macrophage colony stimulating factor (M-CSF/Csf1), which leads to elongation of microglia processes. TNF may also act on neurons by affecting the expression of genes essential in sleep-wake behavior...
July 2015: Brain, Behavior, and Immunity
Kristin A Sauter, Clare Pridans, Anuj Sehgal, Calum C Bain, Charlotte Scott, Lindsey Moffat, Rocío Rojo, Ben M Stutchfield, Claire L Davies, David S Donaldson, Kathleen Renault, Barry W McColl, Alan M Mowat, Alan Serrels, Margaret C Frame, Neil A Mabbott, David A Hume
The MacBlue transgenic mouse uses the Csf1r promoter and first intron to drive expression of gal4-VP16, which in turn drives a cointegrated gal4-responsive UAS-ECFP cassette. The Csf1r promoter region used contains a deletion of a 150 bp conserved region covering trophoblast and osteoclast-specific transcription start sites. In this study, we examined expression of the transgene in embryos and adult mice. In embryos, ECFP was expressed in the large majority of macrophages derived from the yolk sac, and as the liver became a major site of monocytopoiesis...
2014: PloS One
Ishani De, Maria Nikodemova, Megan D Steffen, Emily Sokn, Vilena I Maklakova, Jyoti J Watters, Lara S Collier
Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 overexpressing and control mice...
December 2014: Glia
M Schuberth, J Levin, D Sawalhe, R Schwarzkopf, L von Baumgarten, B Ertl-Wagner, A Rominger, T Arzberger, H A Kretzschmar, T Froböse, J Diehl-Schmid, S Biskup, A Danek
Hereditary diffuse leukencephalopathy with spheroids (HDLS) is a rare progressive form of leukodystrophy with variable clinical presentation and little known pathophysiology. Characteristic pathological features at brain biopsy or postmortem can support the diagnosis. The genetic basis of HDLS was elusive until 2011 when mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as the cause. Mutations in the CSF1R gene had previously been associated with tumor development, including hematological malignancies...
April 2014: Der Nervenarzt
Clare Pridans, Kristin A Sauter, Kristin Baer, Holger Kissel, David A Hume
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line...
2013: Scientific Reports
Malgorzata Sielska, Piotr Przanowski, Bartosz Wylot, Konrad Gabrusiewicz, Marta Maleszewska, Magdalena Kijewska, Malgorzata Zawadzka, Joanna Kucharska, Katyayni Vinnakota, Helmut Kettenmann, Katarzyna Kotulska, Wieslawa Grajkowska, Bozena Kaminska
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...
July 2013: Journal of Pathology
Jian Luo, Fiona Elwood, Markus Britschgi, Saul Villeda, Hui Zhang, Zhaoqing Ding, Liyin Zhu, Haitham Alabsi, Ruth Getachew, Ramya Narasimhan, Rafael Wabl, Nina Fainberg, Michelle L James, Gordon Wong, Jane Relton, Sanjiv S Gambhir, Jeffrey W Pollard, Tony Wyss-Coray
Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia...
January 14, 2013: Journal of Experimental Medicine
Makoto Horiuchi, Kouji Wakayama, Aki Itoh, Kumi Kawai, David Pleasure, Keiko Ozato, Takayuki Itoh
BACKGROUND: Recent fate-mapping studies establish that microglia, the resident mononuclear phagocytes of the CNS, are distinct in origin from the bone marrow-derived myeloid lineage. Interferon regulatory factor 8 (IRF8, also known as interferon consensus sequence binding protein) plays essential roles in development and function of the bone marrow-derived myeloid lineage. However, little is known about its roles in microglia. METHODS: The CNS tissues of IRF8-deficient mice were immunohistochemically analyzed...
2012: Journal of Neuroinflammation
Elisa Gomez Perdiguero, Christian Schulz, Frederic Geissmann
Microglia, macrophages of the central nervous system, play an important role in brain homeostasis. Their origin has been unclear. Recent fate-mapping experiments have established that microglia mostly originate from Myb-independent, FLT3-independent, but PU.1-dependent precursors that express the CSF1-receptor at E8.5 of embryonic development. These precursors are presumably located in the yolk sac (YS) at this time before invading the embryo between E9.5 and E10.5 and colonizing the fetal liver. Indeed, the E14...
January 2013: Glia
Teresa Zelante, Paola Ricciardi-Castagnoli
Most myeloid cells express the growth-factor receptor CSF1R. Recognition of interleukin 34 by CSF1R is required for the development of tissue-resident Langerhans cells and microglia, which explains the independence of their growth from CSF1.
August 2012: Nature Immunology
Yaming Wang, Kristy J Szretter, William Vermi, Susan Gilfillan, Cristina Rossini, Marina Cella, Alexander D Barrow, Michael S Diamond, Marco Colonna
The differentiation of bone marrow-derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy...
August 2012: Nature Immunology
Bryna Erblich, Liyin Zhu, Anne M Etgen, Kostantin Dobrenis, Jeffrey W Pollard
The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain...
2011: PloS One
Sandrine Joly, Mike Francke, Elke Ulbricht, Susanne Beck, Matthias Seeliger, Petra Hirrlinger, Johannes Hirrlinger, Karl S Lang, Martin Zinkernagel, Bernhard Odermatt, Marijana Samardzija, Andreas Reichenbach, Christian Grimm, Charlotte E Remé
Phagocytosis is essential for the removal of photoreceptor debris following retinal injury. We used two mouse models, mice injected with green fluorescent protein-labeled bone marrow cells or green fluorescent protein-labeled microglia, to study the origin and activation patterns of phagocytic cells after acute blue light-induced retinal lesions. We show that following injury, blood-borne macrophages enter the eye via the optic nerve and ciliary body and soon migrate into the injured retinal area. Resident microglia are also activated rapidly throughout the entire retina and adopt macrophage characteristics only in the injured region...
June 2009: American Journal of Pathology
Paula E Cohen, Liyin Zhu, Kayoko Nishimura, Jeffrey W Pollard
Colony stimulating factor 1 (CSF-1) is the primary regulator of cells of the mononuclear phagocytic lineage. Consequently mice lacking CSF-1 (Csf1(op)/Csf1(op)) have depleted populations of macrophages in many tissues. In addition, both sexes have reduced fertility with females having extended estrus cycles and poor ovulation rates, whereas males have low circulating LH and T. In this study, we show that puberty was significantly delayed in Csf1(op)/Csf1(op) females compared with control littermates. Restoration of circulating CSF-1 over the first 2 wk of life accelerated puberty, and this treatment until puberty completely corrected the extended estrous cycles...
April 2002: Endocrinology
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