title: Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.
abstract: 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. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Fiona
authors.initials: F
authors.lastname: Elwood
authors.forename: Markus
authors.initials: M
authors.lastname: Britschgi
authors.forename: Saul
authors.initials: S
authors.lastname: Villeda
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Ding
authors.forename: Liyin
authors.initials: L
authors.lastname: Zhu
authors.forename: Haitham
authors.initials: H
authors.lastname: Alabsi
authors.forename: Ruth
authors.initials: R
authors.lastname: Getachew
authors.forename: Ramya
authors.initials: R
authors.lastname: Narasimhan
authors.forename: Rafael
authors.initials: R
authors.lastname: Wabl
authors.forename: Nina
authors.initials: N
authors.lastname: Fainberg
authors.forename: Michelle L
authors.initials: ML
authors.lastname: James
authors.forename: Gordon
authors.initials: G
authors.lastname: Wong
authors.forename: Jane
authors.initials: J
authors.lastname: Relton
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002470:Cell Survival; D003071:Cognition / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007378:Interleukins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C552364:interleukin-34, mouse; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D007608:Kainic Acid