ORCID Profile
0000-0002-2910-2065
Current Organisation
Albert Einstein College of Medicine
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Publisher: Wiley
Date: 30-07-2023
DOI: 10.1002/GLIA.24446
Abstract: Mutations leading to colony‐stimulating factor‐1 receptor ( CSF‐1R ) loss‐of‐function or haploinsufficiency cause CSF1R‐related leukoencephalopathy (CRL), an adult‐onset disease characterized by loss of myelin and neurodegeneration, for which there is no effective therapy. Symptom onset usually occurs in the fourth decade of life and the penetrance of disease in carriers is high. However, familial studies have identified a few carriers of pathogenic CSF1R mutations that remain asymptomatic even in their seventh decade of life, raising the possibility that the development and severity of disease might be influenced by environmental factors. Here we report new cases in which long‐term glucocorticoid treatment is associated with asymptomatic status in elder carriers of pathogenic CSF‐1R mutations. The main objective of the present study was to investigate the link between chronic immunosuppression initiated pre‐symptomatically and resistance to the development of symptomatic CRL, in the Csf1r +/− mouse model. We show that chronic prednisone administration prevents the development of memory, motor coordination and social interaction deficits, as well as the demyelination, neurodegeneration and microgliosis associated with these deficits. These findings are in agreement with the preliminary clinical observations and support the concept that pre‐symptomatic immunosuppression is protective in patients carrying pathogenic CSF1R variants associated with CRL. Proteomic analysis of microglia and oligodendrocytes indicates that prednisone suppresses processes involved in microglial activation and alleviates senescence and improves fitness of oligodendrocytes. This analysis also identifies new potential targets for therapeutic intervention.
Publisher: American Society of Hematology
Date: 02-07-2015
Publisher: Rockefeller University Press
Date: 26-07-2019
DOI: 10.1084/JEM.20182037
Abstract: Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1–CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-07-2021
Abstract: Recent work has suggested that macrophages may regulate adiposity, but the mechanisms underlying this process remain unresolved. Cox et al. report that a macrophage-derived growth factor, Pvf3, and its receptor on fat body cells are needed for lipid storage in fruit fly larvae (see the Perspective by O'Brien and Domingos). The mouse Pvf3 ortholog, PDGFcc, was similarly required to store fat in newborn and adult mice. When PDGFcc was blocked or deleted, food intake and absorption were normal, but mice increased their energy expenditure partly due to enhanced brown adipose tissue thermogenesis. PDGFcc was produced exclusively by fat-resident macrophages rather than by those mediating inflammation and insulin resistance. This work may inform future treatments for lipodystrophy, cachexia, and obesity. Science , abe9383, this issue p. eabe9383 see also abj5072, p. 24
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2022
DOI: 10.1101/2022.02.21.481325
Abstract: Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r +/- mouse. The expression of Csf2, encoding granulocyte- macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of mouse CRL, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In this manuscript, we investigate the behavioral, electrophysiological and histopathological phenotypes of CRL mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r +/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not their cognitive impairment. Consistent with this, Csf3 heterozygosity attenuated microglial activation in the cerebellum and in the ventral but not in the dorsal hippoc us. Csf3 heterozygosity also failed to prevent demyelination. Csf1r +/- mice exhibited altered synaptic activity in the deep cerebellar nuclei (DCN) associated with increased deposition of the complement factor C1q on glutamatergic synapses and with increased engulfment of glutamatergic synapses by DCN microglia. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3 . Our findings indicate that G-CSF and GM-CSF play non-overlapping roles in mouse CRL development and suggest that G-CSF could be an additional therapeutic target in CRL.
Publisher: Society for Neuroscience
Date: 10-02-2016
DOI: 10.1523/JNEUROSCI.3427-15.2016
Abstract: Previous studies in myelin-mutant mouse models of the inherited and incurable nerve disorder, Charcot-Marie-Tooth (CMT) neuropathy, have demonstrated that low-grade secondary inflammation implicating phagocytosing macrophages lifies demyelination, Schwann cell dedifferentiation and perturbation of axons. The cytokine colony stimulating factor-1 (CSF-1) acts as an important regulator of these macrophage-related disease mechanisms, as genetic and pharmacologic approaches to block the CSF-1/CSF-1R signaling result in a significant alleviation of pathological alterations in mutant peripheral nerves. In mouse models of CMT1A and CMT1X, as well as in human biopsies, CSF-1 is predominantly expressed by endoneurial fibroblasts, which are closely associated with macrophages, suggesting local stimulatory mechanisms. Here we investigated the impact of cell-surface and secreted isoforms of CSF-1 on macrophage-related disease in connexin32-deficient ( Cx32def ) mice, a mouse model of CMT1X. Our present observations suggest that the secreted proteoglycan isoform (spCSF-1) is predominantly expressed by fibroblasts, whereas the membrane-spanning cell-surface isoform (csCSF-1) is expressed by macrophages. Using crossbreeding approaches to selectively restore or overexpress distinct isoforms in CSF-1-deficient (osteopetrotic) Cx32def mice, we demonstrate that both isoforms equally regulate macrophage numbers dose-dependently. However, spCSF-1 mediates macrophage activation and macrophage-related neural damage, whereas csCSF-1 inhibits macrophage activation and attenuates neuropathy. These results further corroborate the important role of secondary inflammation in mouse models of CMT1 and might identify specific targets for therapeutic approaches to modulate innate immune reactions. SIGNIFICANCE STATEMENT Mouse models of Charcot-Marie-Tooth neuropathy have indicated that low-grade secondary inflammation involving phagocytosing macrophages lifies demyelination, Schwann cell dedifferentiation, and perturbation of axons. The recruitment and pathogenic activation of detrimental macrophages is regulated by CSF-1, a cytokine that is mostly expressed by fibroblasts in the diseased nerve and exists in three isoforms. We show that the cell-surface and secreted isoforms of CSF-1 have opposing effects on macrophage activation and disease progression in a mouse model of CMT1X. These insights into opposing functions of disease-modulating cytokine isoforms might enable the development of specific therapeutic approaches.
Publisher: Wiley
Date: 05-07-2021
DOI: 10.1111/FEBS.16085
Abstract: The role of colony‐stimulating factor‐1 receptor (CSF‐1R) in macrophage and organismal development has been extensively studied in mouse. Within the last decade, mutations in the CSF1R have been shown to cause rare diseases of both pediatric (Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis, OMIM #618476) and adult (CSF1R‐related leukoencephalopathy, OMIM #221820) onset. Here we review the genetics, penetrance, and histopathological features of these diseases and discuss to what extent the animal models of Csf1r deficiency currently available provide systems in which to study the underlying mechanisms involved.
Publisher: Wiley
Date: 20-10-2020
DOI: 10.1002/GLIA.23929
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Society of Hematology
Date: 19-02-2015
DOI: 10.1182/BLOOD-2014-10-608000
Abstract: Analysis of CSF-1R pTyr-regulated messenger RNAs identifies novel signaling nodes and networks that can be targeted to modulate macrophage functions. miR-21 is a novel CSF-1R pTyr-721–induced molecule that suppresses the macrophage M1 phenotype and enhances the M2 phenotype.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 26-11-2022
DOI: 10.1002/GLIA.24310
Abstract: Colony stimulating factor (CSF) receptor‐1 (CSF‐1R)‐related leukoencephalopathy (CRL) is an adult‐onset, demyelinating and neurodegenerative disease caused by autosomal dominant mutations in CSF1R , modeled by the Csf1r +/− mouse. The expression of Csf2 , encoding granulocyte‐macrophage CSF (GM‐CSF) and of Csf3 , encoding granulocyte CSF (G‐CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of Csf1r +/− mice, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In the present study, we investigate the behavioral, electrophysiological and histopathological phenotypes of Csf1r +/− mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r +/− mouse brains and ameliorated anxiety‐like behavior, motor coordination and social interaction deficits, but not the cognitive impairment of Csf1r +/− mice. Csf3 heterozygosity failed to prevent callosal demyelination. However, consistent with its effects on behavior, Csf3 heterozygosity normalized microglial morphology in the cerebellum and in the ventral, but not in the dorsal hippoc us. Csf1r +/− mice exhibited altered firing activity in the deep cerebellar nuclei (DCN) associated with increased engulfment of glutamatergic synapses by DCN microglia and increased deposition of the complement factor C1q on glutamatergic synapses. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3 . Our current and earlier findings indicate that G‐CSF and GM‐CSF play largely non‐overlapping roles in CRL‐like disease development in Csf1r +/− mice.
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2020
DOI: 10.1101/2020.06.15.152397
Abstract: Macrophages control inflammation in obese animals, and may also directly or indirectly regulate energy storage. In a genetic screen we identify a PDGF-family growth factor, Pvf3 , produced by macrophages and required for lipid storage in Drosophila larvae’s fat body cells. We next demonstrate using genetic and pharmacological approaches that Pvf3 ortholog PDGFcc, produced by Ccr2 -independent embryo-derived tissue macrophages, is also required for storage in mammalian white adipose tissue. PDGFcc production by resident macrophages is regulated by diet, acts on white adipocytes in a paracrine manner, and controls adipocyte hypertrophy in high-fat diet fed and genetically hyperphagic mice. Upon PDGFcc blockade, excess lipids are redirected at the organismal level toward thermogenesis and hepatic storage in adults. This process is altogether independent from inflammation and insulin resistance promoted by Ccr2 -dependent monocytes/macrophages. Our data identify a conserved macrophagedependent mechanism that controls energy storage, conducive to the design of pharmacological interventions.
Location: Australia
Location: United States of America
Location: Australia
Location: Australia
Location: United States of America
No related grants have been discovered for E. Richard Stanley.