Редактирование: CSF1R

Macrophage colony-stimulating factor 1 receptor precursor (CSF-1 receptor) (EC 2.7.10.1) (CSF-1-R) (CSF-1R) (M-CSF-R) (Proto-oncogene c-Fms) (CD115 antigen) [FMS]

==Publications==

{{medline-entry
|title=[[CSF1R]] blockade induces macrophage ablation and results in mouse choroidal vascular atrophy and [[RPE]] disorganization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32234210
|abstract=The choroid, which provides vascular supply to the outer retina, demonstrates progressive degeneration in aging and age-related macular degeneration (AMD). However mechanisms that maintain or compromise choroidal homeostasis are obscure. We discovered that the ablation of choroidal macrophages via [[CSF1R]] blockade was associated with choroidal vascular atrophy and retinal pigment epithelial ([[RPE]]) changes including structural disruption, downregulation of visual cycle genes, and altered angiogenic factor expression. Suspending [[CSF1R]] blockade following ablation enabled spontaneous macrophage regeneration, which fully restored original macrophage distributions and morphologies. Macrophage regeneration was accompanied by arrested vascular degeneration and ameliorated pathological [[RPE]] alterations. These findings suggest that choroidal macrophages play a previously unappreciated trophic role in maintaining choroidal vasculature and [[RPE]] cells, implicating insufficiency in choroidal macrophage function as a factor in aging- and AMD-associated pathology. Modulating macrophage function may constitute a strategy for the therapeutic preservation of the choroid and [[RPE]] in age-related retinal disorders.

|keywords=* RPE disorganization
* aging
* choroid
* choroidal macrophage
* choroidal vasculature
* immunology
* inflammation
* mouse
* neuroscience
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156269
}}
{{medline-entry
|title=[[CSF1R]] inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32007953
|abstract=As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the [[CSF1R]] inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to [[CSF1R]] inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

|keywords=* CSF1R
* adipose
* aging
* environmental enrichment
* microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041757
}}
{{medline-entry
|title=Modulation of Microglia by Voluntary Exercise or [[CSF1R]] Inhibition Prevents Age-Related Loss of Functional Motor Units.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31693894
|abstract=Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by [[CSF1R]] inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss.
|mesh-terms=* Aging
* Animals
* Cell Line
* Databases, Genetic
* Humans
* Induced Pluripotent Stem Cells
* Macrophages
* Male
* Mice
* Mice, Inbred C57BL
* Microglia
* Motor Neurons
* Muscle, Skeletal
* Neuromuscular Junction
* Neuronal Plasticity
* Physical Conditioning, Animal
* RNA-Seq
* Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
* Spinal Cord
|keywords=* CSF1R inhibition
* aging
* exercise
* innervation
* microglia
* motor unit
* neuroinflammation
* neuromuscular junction
* neuromuscular system
* spinal cord
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2019.10.003
}}
{{medline-entry
|title=Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30477578
|abstract=Microglia are the resident innate immune cells of the central nervous system. Limited turnover throughout the lifespan leaves microglia susceptible to age-associated dysfunction. Indeed, we and others have reported microglia develop a pro-inflammatory or "primed" profile with age, characterized by increased expression of inflammatory mediators (e.g., MHC-II, [[CD68]], IL-1β). Moreover, immune challenge with lipopolysaccharide (LPS) causes an exaggerated and prolonged neuroinflammatory response mediated by primed microglia in the aged brain. Recent studies show colony-stimulating factor 1 receptor ([[CSF1R]]) antagonism results in rapid depletion of microglia without significant complications. Therefore, we hypothesized that [[CSF1R]] antagonist-mediated depletion of microglia in the aged brain would result in repopulation with new and unprimed microglia. Here we provide novel evidence that microglia in the brain of adult (6-8 weeks old) and aged (16-18 months old) BALB/c mice were depleted following 3-week oral PLX5622 administration. When [[CSF1R]] antagonism was stopped, microglia repopulated equally in the adult and aged brain. Microglial depletion and repopulation reversed age-associated increases in microglial [[CD68]]  lysosome enlargement and lipofuscin accumulation. Microglia-specific RNA sequencing revealed 511 differentially expressed genes with age. Of these, 117 genes were reversed by microglial repopulation (e.g., Apoe, Tgfb2, Socs3). Nevertheless, LPS challenge still induced an exaggerated microglial inflammatory response in the aged brain compared to adults. RNA sequencing of whole-brain tissue revealed an age-induced inflammatory signature, including reactive astrocytes, that was not restored by microglial depletion and repopulation. Furthermore, the microenvironment of the aged brain produced soluble factors that influenced developing microglia ex vivo and induced a profile primed to LPS challenge. Thus, the aged brain microenvironment promotes microglial priming despite repopulation of new microglia. Collectively, aged microglia proliferate and repopulate the brain, but these new cells still adopt a pro-inflammatory profile in the aged brain.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Brain
* CD11b Antigen
* Cell Proliferation
* Gene Expression Regulation
* Glial Fibrillary Acidic Protein
* Humans
* Leukocyte Common Antigens
* Lipofuscin
* Lipopolysaccharides
* Male
* Mice
* Mice, Inbred BALB C
* Microglia
* Organic Chemicals
* RNA, Messenger
* Social Behavior
|keywords=* Age
* CSF1R antagonist
* Lipopolysaccharide
* Microglia
* Priming
* RNA-Seq
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260864
}}
{{medline-entry
|title=Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30276955
|abstract=Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor ([[CSF1R]]). Withdrawal of [[CSF1R]] inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a "primed" phenotype and studies indicate that this coincides with age-related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using [[CSF1R]] inhibitor-induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation-related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age-related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age-related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age-induced deficits in long-term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.
|mesh-terms=* Aging
* Animals
* Cell Count
* Cell Shape
* Cognition
* Cytoskeleton
* Dendritic Spines
* Gene Expression Regulation
* Inflammation
* Lipopolysaccharides
* Long-Term Potentiation
* Male
* Mice, Inbred C57BL
* Microglia
* Neurogenesis
* Neurons
* Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
* Synapses
|keywords=* aging
* colony-stimulating factor 1 receptor
* long-term potentiation
* microglia
* plx5622
* repopulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260908
}}
{{medline-entry
|title=Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of [[CSF1R]] and [[NOTCH3]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29544907
|abstract=Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in [[NOTCH3]], [[HTRA1]], [[TREX1]], [[ARSA]], [[CSF1R]], [[EIF2B1]], [[EIF2B2]], [[EIF2B3]], [[EIF2B4]], and [[EIF2B5]], respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in [[CSF1R]] TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, [[NOTCH3]] was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between [[NOTCH3]], [[CSF1R]], and sporadic late-onset AD, which warrants further investigation.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Animals
* Cerebral Cortex
* Cohort Studies
* European Continental Ancestry Group
* Female
* Genetic Association Studies
* Hippocampus
* Humans
* Leukodystrophy, Metachromatic
* Male
* Mice
* Middle Aged
* Mutation
* Receptor, Notch3
* Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
* Risk Factors
|keywords=* Alzheimer's disease
* CSF1R
* Mendelian leukodystrophies
* NOTCH3
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937905
}}
{{medline-entry
|title=Pleiotropic effects of extended blockade of [[CSF1]]R signaling in adult mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24652541
|abstract=We investigated the role of [[CSF1]]R signaling in adult mice using prolonged treatment with anti-[[CSF1]]R antibody. Mutation of the [[CSF1]] gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the [[CSF1]]R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of [[CSF1]]R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-[[CSF1]]R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for [[CSF1]]R signaling in macrophage and OCL homeostasis but indicate that most effects of [[CSF1]] and [[CSF1]]R mutations are due to effects on development. 
|mesh-terms=* Aging
* Animals
* Female
* Goblet Cells
* Homeostasis
* Insulin-Secreting Cells
* Interleukins
* Macrophages
* Male
* Mice
* Mice, Mutant Strains
* Mutation
* Paneth Cells
* Receptor, Macrophage Colony-Stimulating Factor
* Sex Characteristics
* Signal Transduction
* Testis
|keywords=* Kupffer
* Paneth
* bone
* macrophage
* osteoclast
* testis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378363
}}