37 results on '"Grabert, Kathleen"'
Search Results
2. Ciita Regulates Local and Systemic Immune Responses in a Combined rAAV-α-synuclein and Preformed Fibril-Induced Rat Model for Parkinson’s Disease
- Author
-
Fredlund, Filip, primary, Jimenez-Ferrer, Itzia, additional, Grabert, Kathleen, additional, Belfiori, Lautaro, additional, Luk, Kelvin C., additional, and Swanberg, Maria, additional
- Published
- 2024
- Full Text
- View/download PDF
3. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations.
- Author
-
Rojo, Rocío, Raper, Anna, Ozdemir, Derya D, Lefevre, Lucas, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Bradford, Barry, Caruso, Melanie, Gazova, Iveta, Sánchez, Alejandra, Lisowski, Zofia M, Alves, Joana, Molina-Gonzalez, Irene, Davtyan, Hayk, Lodge, Rebecca J, Glover, James D, Wallace, Robert, Munro, David AD, David, Eyal, Amit, Ido, Miron, Véronique E, Priller, Josef, Jenkins, Stephen J, Hardingham, Giles E, Blurton-Jones, Mathew, Mabbott, Neil A, Summers, Kim M, Hohenstein, Peter, Hume, David A, and Pridans, Clare
- Subjects
Microglia ,Monocytes ,Macrophages ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mice ,Disease Models ,Animal ,Epidermal Growth Factor ,Macrophage Colony-Stimulating Factor ,Receptors ,Granulocyte-Macrophage Colony-Stimulating Factor ,Cell Differentiation ,Cell Proliferation ,Phagocytosis ,Gene Expression Regulation ,Sequence Deletion ,Base Sequence ,Regulatory Sequences ,Nucleic Acid ,Genes ,fms ,Female ,Male ,Embryonic Stem Cells ,RAW 264.7 Cells ,Inbred C57BL ,Knockout ,Disease Models ,Animal ,Receptors ,Granulocyte-Macrophage Colony-Stimulating Factor ,Regulatory Sequences ,Nucleic Acid ,Genes ,fms ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,MD Multidisciplinary - Abstract
The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r-/- rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.
- Published
- 2019
4. SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome–lysosome fusion
- Author
-
González-Rodríguez, Patricia, Delorme-Axford, Elizabeth, Bernard, Amélie, Keane, Lily, Stratoulias, Vassilis, Grabert, Kathleen, Engskog-Vlachos, Pinelopi, Füllgrabe, Jens, Klionsky, Daniel J., and Joseph, Bertrand
- Published
- 2022
- Full Text
- View/download PDF
5. Defining microglial phenotypic diversity and the impact of ageing
- Author
-
Grabert, Kathleen, McColl, Barry, and Summers, Kim
- Subjects
612.8 ,microglia ,ageing ,phenotype - Abstract
Microglia are the resident macrophages of the central nervous system (CNS) and, as key immune effector cells, form the first line of defence. Microglial cells also provide support for maintaining neuronal homeostasis and more generally normal brain physiology and cognitive function. It has been speculated that in order to support homeostasis, microglia adapt to a variety of brain microenvironments leading to regional phenotypic heterogeneity. To date this hypothesis lacks convincing empirical evidence, yet is critical to better understand microglial function in health and age-related neurodegenerative disease. In 2010 it was estimated that in the UK approximately 10 million people are over the age of 65, which is expected to double by 2050. Ageing is one of the strongest risk factors for neurodegenerative diseases such as Alzheimer’s and Parkinson‘s disease and growing evidence implicates neuroinflammatory mechansims that may involve microglial dysfunction in disease aetiology. The majority of age-related neurodegenerative diseases develop in a region-specific manner but the reasons are poorly understood. Accordingly, the work described in this thesis sought to determine the extent and nature of regional transcriptional heterogeneity of microglia and how this is affected by ageing. To examine the function and phenotype of these cells a technique for isolating pure microglia from the adult mouse brain was established. Microglia were consistently extracted by density-gradient and immunomagnetic cell separation. In vitro assays showed purified microglia retained key functional properties including phagocytosis, polarisation and production of pro-inflammatory cytokines in response to exogenous stimulation. Thus, freshly isolated microglia are not altered or dysfunctional during the extraction process and are likely to adequately represent the 'real' in vivo state. Genome-wide transcriptional network analysis of young adult mouse microglia from four discrete regions of the brain (cerebellum, cerebral cortex, hippocampus and striatum) uncovered regional heterogeneity in the microglial transcriptome driven particularly by bioenergetic and immunoregulatory functions. Transcriptional profiles of cerebellar and hippocampal microglia suggest a higher immune vigilance and alertness, which was supported by functional differences in the capability of microglia to phagocytose and control replication of bacteria. Region-dependent heterogeneity of microglia was largely consistent throughout the ageing process; however the region-specific phenotypes were more pronounced as age increased indicating region-dependent kinetics of microglial ageing. Collectively, the outcome of this study implies that microglia adapt to region-specific demands of brain tissue under steady-state conditions and are susceptible to ageing. Region was found to have a greater impact on microglial diversity than age. Overall, these findings will generate a substantial advance in our understanding of microglial function in the healthy brain and in age-related neurodegeneration.
- Published
- 2015
6. Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response
- Author
-
Friess, Lara, Cheray, Mathilde, Keane, Lily, Grabert, Kathleen, and Joseph, Bertrand
- Published
- 2021
- Full Text
- View/download PDF
7. CiitaRegulates Local and Systemic Immune Responses in a Combined rAAV-a-synuclein and Preformed Fibril-Induced Rat Model for Parkinson’s Disease
- Author
-
Fredlund, Filip, Jimenez-Ferrer, Itzia, Grabert, Kathleen, Belfiori, Lautaro Francisco, Luk, Kelvin, and Swanberg, Maria
- Abstract
Background: Parkinson’s disease (PD) is characterized by alpha-synuclein (a-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and a-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciitalevels significantly increase a-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in a-Syn-induced rat PD models.Objective: Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciitalevels (DA.VRA4) compared to the background strain (DA).Methods: To model PD, we combined rAAV-mediated a-Syn overexpression in the substantia nigra with striatal injection of a-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection.Results: Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to a-Syn and only subtle Ciita- and/or a-Syn-dependent changes in the T lymphocyte compartment. Lower Ciitalevels were consistently associated with higher TNF levels in serum.Conclusions: Ciitaregulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD.
- Published
- 2024
- Full Text
- View/download PDF
8. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
-
Stratoulias, Vassilis, primary, Ruiz, Rocío, additional, Kanatani, Shigeaki, additional, Osman, Ahmed M., additional, Keane, Lily, additional, Armengol, Jose A., additional, Rodríguez-Moreno, Antonio, additional, Murgoci, Adriana-Natalia, additional, García-Domínguez, Irene, additional, Alonso-Bellido, Isabel, additional, González Ibáñez, Fernando, additional, Picard, Katherine, additional, Vázquez-Cabrera, Guillermo, additional, Posada-Pérez, Mercedes, additional, Vernoux, Nathalie, additional, Tejera, Dario, additional, Grabert, Kathleen, additional, Cheray, Mathilde, additional, González-Rodríguez, Patricia, additional, Pérez-Villegas, Eva M., additional, Martínez-Gallego, Irene, additional, Lastra-Romero, Alejandro, additional, Brodin, David, additional, Avila-Cariño, Javier, additional, Cao, Yang, additional, Airavaara, Mikko, additional, Uhlén, Per, additional, Heneka, Michael T., additional, Tremblay, Marie-Ève, additional, Blomgren, Klas, additional, Venero, Jose L., additional, and Joseph, Bertrand, additional
- Published
- 2023
- Full Text
- View/download PDF
9. The MHC class II transactivator affects local and systemic immune responses in an α-synuclein seeded rat model for Parkinson’s disease
- Author
-
Bäckström, Filip, primary, Jimenez-Ferrer, Itzia, additional, Grabert, Kathleen, additional, Belfiori, Lautaro, additional, Luk, Kelvin, additional, and Swanberg, Maria, additional
- Published
- 2023
- Full Text
- View/download PDF
10. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
-
Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, Jose A., Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel, González Ibáñez, Fernando, Picard, Katherine, Vázquez-Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva M., Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Avila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, Jose L., Joseph, Bertrand, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, Jose A., Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel, González Ibáñez, Fernando, Picard, Katherine, Vázquez-Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva M., Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Avila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, Jose L., and Joseph, Bertrand
- Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1– microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
- Published
- 2023
- Full Text
- View/download PDF
11. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
-
Karolinska Institute, Swedish Research Council, Swedish Brain Foundation, Sigrid Juselius Foundation, Academy of Finland, Swedish Cultural Foundation, Swedish Cancer Society, Consejo Nacional de Ciencia y Tecnología (México), Fonds de la Recherche en Sante du Québec, Wenner-Gren Foundation, Ake Wiberg Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Junta de Andalucía, Swedish Childhood Cancer Foundation, Canada Research Chairs, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, José Ángel, Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel María, González Ibáñez, Fernando, Picard, Katherine, Vázquez Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva María, Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Ávila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, José L., Joseph, Bertrand, Karolinska Institute, Swedish Research Council, Swedish Brain Foundation, Sigrid Juselius Foundation, Academy of Finland, Swedish Cultural Foundation, Swedish Cancer Society, Consejo Nacional de Ciencia y Tecnología (México), Fonds de la Recherche en Sante du Québec, Wenner-Gren Foundation, Ake Wiberg Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Junta de Andalucía, Swedish Childhood Cancer Foundation, Canada Research Chairs, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, José Ángel, Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel María, González Ibáñez, Fernando, Picard, Katherine, Vázquez Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva María, Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Ávila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, José L., and Joseph, Bertrand
- Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1- microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
- Published
- 2023
12. CiitaRegulates Local and Systemic Immune Responses in a Combined rAAV-α-synuclein and Preformed Fibril-Induced Rat Model for Parkinson’s Disease
- Author
-
Fredlund, Filip, Jimenez-Ferrer, Itzia, Grabert, Kathleen, Belfiori, Lautaro, Luk, Kelvin C., and Swanberg, Maria
- Abstract
Parkinson’s disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciitalevels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn-induced rat PD models. Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciitalevels (DA.VRA4) compared to the background strain (DA). To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection. Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtle Ciita- and/or α-Syn-dependent changes in the T lymphocyte compartment. Lower Ciitalevels were consistently associated with higher TNF levels in serum. Ciitaregulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD. Parkinson’s disease is characterized by loss of nerve cells. There is also abnormal aggregation of a protein called alpha-synuclein and an ongoing inflammatory response. Findings that immune cells in the blood of individuals with Parkinson’s disease react against the alpha-synuclein protein and that genes important for the immune system affect the risk of developing Parkinson’s disease indicate that immune responses are important in Parkinson’s disease. We have previously found that a low expression of certain immune molecules worsens disease progression in a rat model of Parkinson’s disease. The aim of this study was to identify changes in the immune system in rats that are associated with disease severity, to identify mechanisms that could be targeted to treat Parkinson’s disease. To model Parkinson’s disease, we injected a modified virus to produce large amounts of alpha-synuclein combined with an injection of aggregated alpha-synuclein proteins in the rat brain. The model mimics several features of Parkinson’s disease including nerve cell death, problems with movement, accumulation of alpha-synuclein in the brain, and an immune response. We observed that the immune system in the brain and blood responded to the model but that differences were small compared to controls. Our results suggest that small changes in the immune system can have a large effect on disease progression and that therapies targeting the immune system are worth exploring to find better treatment for Parkinson’s disease.
- Published
- 2024
- Full Text
- View/download PDF
13. Isolation and Phenotyping of Adult Mouse Microglial Cells
- Author
-
Grabert, Kathleen, primary and McColl, Barry W., additional
- Published
- 2018
- Full Text
- View/download PDF
14. The MHC class II transactivator affects local and systemic immune responses in an α-synuclein seeded rat model for Parkinson’s disease
- Author
-
Bäckström, Filip, primary, Jimenez-Ferrer, Itzia, additional, Grabert, Kathleen, additional, Belifori, Lautaro, additional, Luk, Kelvin C., additional, and Swanberg, Maria, additional
- Published
- 2022
- Full Text
- View/download PDF
15. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
- Author
-
Stables, Jennifer, Green, Emma, Sehgal, Anuj, Patkar, Omkar, Keshvari, Sahar, Taylor, Isis, Ashkroft, Maisie, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Szymkowiak, Stefan, McColl, Barry, Adamson, Antony, Humphreys, Neil, Mueller, Werner, Starobova, Hana, Vetter, Irinia, Shabestari, Sepideh Kiani, Blurton-Jones, Matthew, Summers, Kim, Irvine, Katharine, Pridans, Clare, Hume, David, Stables, Jennifer, Green, Emma, Sehgal, Anuj, Patkar, Omkar, Keshvari, Sahar, Taylor, Isis, Ashkroft, Maisie, Grabert, Kathleen, Wollscheid-Lengeling, Evi, Szymkowiak, Stefan, McColl, Barry, Adamson, Antony, Humphreys, Neil, Mueller, Werner, Starobova, Hana, Vetter, Irinia, Shabestari, Sepideh Kiani, Blurton-Jones, Matthew, Summers, Kim, Irvine, Katharine, Pridans, Clare, and Hume, David
- Abstract
Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
- Published
- 2022
16. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
- Author
-
Stables, Jennifer, primary, Green, Emma K., additional, Sehgal, Anuj, additional, Patkar, Omkar L., additional, Keshvari, Sahar, additional, Taylor, Isis, additional, Ashcroft, Maisie E., additional, Grabert, Kathleen, additional, Wollscheid-Lengeling, Evi, additional, Szymkowiak, Stefan, additional, McColl, Barry W., additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Mueller, Werner, additional, Starobova, Hana, additional, Vetter, Irina, additional, Shabestari, Sepideh Kiani, additional, Blurton-Jones, Matthew M., additional, Summers, Kim M., additional, Irvine, Katharine M., additional, Pridans, Clare, additional, and Hume, David A., additional
- Published
- 2022
- Full Text
- View/download PDF
17. A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant-negative impact on CSF1R signaling
- Author
-
Stables, Jennifer, primary, Green, Emma K., additional, Sehgal, Anuj, additional, Patkar, Omkar, additional, Keshvari, Sahar, additional, Taylor, Isis, additional, Ashcroft, Maisie E., additional, Grabert, Kathleen, additional, Wollscheid-Lengeling, Evi, additional, Szymkowiak, Stefan, additional, McColl, Barry W., additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Mueller, Werner, additional, Starobova, Hana, additional, Vetter, Irina, additional, Shabestari, Sepideh Kiani, additional, Blurton-Jones, Matthew M., additional, Summers, Kim M., additional, Irvine, Katharine M., additional, Pridans, Clare, additional, and Hume, David A., additional
- Published
- 2021
- Full Text
- View/download PDF
18. Arg1+ microglia are critical for shaping cognition in female mice
- Author
-
Stratoulias, Vassilis, primary, Ruiz, Rocío, additional, Kanatani, Shigeaki, additional, Osman, Ahmed M., additional, Armengol, Jose A., additional, Rodríguez-Moreno, Antonio, additional, Murgoci, Adriana-Natalia, additional, García-Domínguez, Irene, additional, Keane, Lily, additional, Vázquez-Cabrera, Guillermo, additional, Alonso-Bellido, Isabel, additional, Vernoux, Nathalie, additional, Tejera, Dario, additional, Grabert, Kathleen, additional, Cheray, Mathilde, additional, González-Rodríguez, Patricia, additional, Pérez-Villegas, Eva M., additional, Martinez-Gallego, Irene, additional, Brodin, David, additional, Avila-Cariño, Javier, additional, Airavaara, Mikko, additional, Uhlén, Per, additional, Heneka, Michael T., additional, Tremblay, Marie-Ève, additional, Blomgren, Klas, additional, Venero, Jose L., additional, and Joseph, Bertrand, additional
- Published
- 2021
- Full Text
- View/download PDF
19. Additional file 1 of Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response
- Author
-
Friess, Lara, Cheray, Mathilde, Keane, Lily, Grabert, Kathleen, and Joseph, Bertrand
- Abstract
Additional file 1: Figure S1. Reduction in Atg7 expression decreases the ability of BV2 microglia to undergo autophagy. a) Immunoblot analysis and b) quantification of LC3-I and LC3-II expression versus ACTB in shCtrl BV2 cells versus shAtg7 BV2 cells. Cells were cultured in EBSS medium to induce starvation, or stimulated with 250 nM Torin1 for 2 h, to induce autophagy. Treatment with BafA1 (40 nM), late inhibitor of autophagy, before sample collection was used to block the autophagic flux. c) Comparison of Nos2 mRNA expression measured by RT-qPCR in shAtg7 and shCtrl BV2 cells. Cells were pre-treated with BafA1 (40 nM) for 30 min and then treated with LPS (100 ng/ml) for 3 h. Values are a mean of 3 (c) or 4 (b) independent experiments �� SEM and considered significant for *p
- Published
- 2021
- Full Text
- View/download PDF
20. A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system
- Author
-
Grabert, Kathleen, Sehgal, Anuj, Irvine, Katherine, Wollscheid-Lengeling, Evi, Rojo, Rocio, Ozedmir, Derya, Stables Jen, Luke, Gary, Ryan, Martin, Adamson, Antony, Humphreys, Neil, Sandrock, Cheyenne, Verkasalo, Veera, Mueller, Werner, Hohenstein, Peter, Pettit, Allison, Pridans, Clare, Hume, David, Grabert, Kathleen, Sehgal, Anuj, Irvine, Katherine, Wollscheid-Lengeling, Evi, Rojo, Rocio, Ozedmir, Derya, Stables Jen, Luke, Gary, Ryan, Martin, Adamson, Antony, Humphreys, Neil, Sandrock, Cheyenne, Verkasalo, Veera, Mueller, Werner, Hohenstein, Peter, Pettit, Allison, Pridans, Clare, and Hume, David
- Abstract
The proliferation, differentiation, and survival of cells of the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, and classical dendritic cells) are controlled by signals from the M-CSF receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters, but none is both universal and lineage restricted. In this article, we report the development and characterization of a CSF1R reporter mouse. A FusionRed (FRed) cassette was inserted in-frame with the C terminus of CSF1R, separated by a T2A-cleavable linker. The insertion had no effect of CSF1R expression or function. CSF1R-FRed was expressed in monocytes and macrophages and absent from granulocytes and lymphocytes. In bone marrow, CSF1R-FRed was absent in lineage-negative hematopoietic stem cells, arguing against a direct role for CSF1R in myeloid lineage commitment. It was highly expressed in marrow monocytes and common myeloid progenitors but significantly lower in granulocyte-macrophage progenitors. In sections of bone marrow, CSF1R-FRed was also detected in osteoclasts, CD169+ resident macrophages, and, consistent with previous mRNA analysis, in megakaryocytes. In lymphoid tissues, CSF1R-FRed highlighted diverse MPS populations, including classical dendritic cells. Whole mount imaging of nonlymphoid tissues in mice with combined CSF1R-FRed/Csf1r-EGFP confirmed the restriction of CSF1R expression to MPS cells. The two markers highlight the remarkable abundance and regular distribution of tissue MPS cells, including novel macrophage populations within tendon and skeletal muscle and underlying the mesothelial/serosal/capsular surfaces of every major organ. The CSF1R-FRed mouse provides a novel reporter with exquisite specificity for cells of the MPS.
- Published
- 2020
21. The Rules of Engagement : Do Microglia Seal the Fate in the Inverse Relation of Glioma and Alzheimer's Disease?
- Author
-
Cheray, Mathilde, Stratoulias, Vassilis, Joseph, Bertrand, Grabert, Kathleen, and Neuroscience Center
- Subjects
NEUROPILIN 1 ,EXPRESSION ,3112 Neurosciences ,COMMON VARIANTS ,Alzheimer's disease ,PHENOTYPE ,IDENTIFIES VARIANTS ,CANCER ,APOLIPOPROTEIN-E ,3124 Neurology and psychiatry ,risk genes ,inverse correlation ,glioma ,ENDOTHELIAL GROWTH-FACTOR ,disease-associated microglia ,GENOME-WIDE ASSOCIATION ,MACROPHAGES - Abstract
Microglia, the immune cells of the brain, play a major role in the maintenance of brain homeostasis and constantly screen the brain environment to detect any infection or damage. Once activated by a stimulus, microglial cells initiate an immune response followed by the resolution of brain inflammation. A failure or deviation in the housekeeping function of these guardian cells can lead to multiple diseases, including brain cancer and neurodegenerative diseases such as Alzheimer's disease (AD). A small number of studies have investigated the causal relation of both diseases, thereby revealing an inverse relationship where cancer patients have a reduced risk to develop AD and vice versa. In this review, we aim to shed light on the role of microglia in the fate to develop specifically glioma as one type of cancer or AD. We will examine the common and/or opposing genetic predisposition as well as associated pathways of these diseases to unravel a possible involvement of microglia in the occurrence of either disease. Lastly, a set of guidelines will be proposed for future research and diagnostics to clarify and improve the knowledge on the role of microglia in the decision toward one pathology or another.
- Published
- 2019
22. Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System
- Author
-
Hawley, Catherine A., Rojo, Rocio, Raper, Anna, Sauter, Kristin A., Lisowski, Zofia M., Grabert, Kathleen, Bain, Calum C., Davis, Gemma M., Louwe, Pieter A., Ostrowski, Michael C., Hume, David A., Pridans, Clare, and Jenkins, Stephen J.
- Subjects
Novel Immunological Methods ,Immunology ,Medicine and Health Sciences ,Biology and Life Sciences ,Immunology and Allergy - Abstract
CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r-mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified ΔCsf1-enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r-driven reporter lines, Csf1r-mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double ΔCsf1r-ECFP-Csf1r-mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r-mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines.
- Published
- 2018
23. Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas
- Author
-
Keane, Lily, primary, Cheray, Mathilde, additional, Saidi, Dalel, additional, Kirby, Caoimhe, additional, Friess, Lara, additional, Gonzalez-Rodriguez, Patricia, additional, Gerdes, Maren Elisabeth, additional, Grabert, Kathleen, additional, McColl, Barry W, additional, and Joseph, Bertrand, additional
- Published
- 2021
- Full Text
- View/download PDF
24. A Transgenic Line That Reports CSF1R Protein Expression Provides a Definitive Marker for the Mouse Mononuclear Phagocyte System
- Author
-
Grabert, Kathleen, primary, Sehgal, Anuj, additional, Irvine, Katharine M., additional, Wollscheid-Lengeling, Evi, additional, Ozdemir, Derya D., additional, Stables, Jennifer, additional, Luke, Garry A., additional, Ryan, Martin D., additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Sandrock, Cheyenne J., additional, Rojo, Rocio, additional, Verkasalo, Veera A., additional, Mueller, Werner, additional, Hohenstein, Peter, additional, Pettit, Allison R., additional, Pridans, Clare, additional, and Hume, David A., additional
- Published
- 2020
- Full Text
- View/download PDF
25. Isolation and Phenotyping of Adult Mouse Microglial Cells v1
- Author
-
Grabert, Kathleen, primary and W. McColl, Barry, additional
- Published
- 2020
- Full Text
- View/download PDF
26. Complex deletion and proximal reinsertion of a 150bp regulatory sequence in the mouse Csf1r promoter mediated by CRISPR-Cas9
- Author
-
Summers, Kim M., primary, Pridans, Clare, additional, Wollscheid-Lengeling, Evi, additional, Grabert, Kathleen, additional, Adamson, Antony, additional, Humphreys, Neil E., additional, Irvine, Katharine M., additional, and Hume, David A., additional
- Published
- 2019
- Full Text
- View/download PDF
27. The Rules of Engagement: Do Microglia Seal the Fate in the Inverse Relation of Glioma and Alzheimer’s Disease?
- Author
-
Cheray, Mathilde, primary, Stratoulias, Vassilis, additional, Joseph, Bertrand, additional, and Grabert, Kathleen, additional
- Published
- 2019
- Full Text
- View/download PDF
28. Correction: Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus
- Author
-
Pridans, Clare, primary, Raper, Anna, additional, Davis, Gemma M., additional, Alves, Joana, additional, Sauter, Kristin A., additional, Lefevre, Lucas, additional, Regan, Tim, additional, Meek, Stephen, additional, Sutherland, Linda, additional, Thomson, Alison J., additional, Clohisey, Sara, additional, Bush, Stephen J., additional, Rojo, Rocío, additional, Lisowski, Zofia M., additional, Wallace, Robert, additional, Grabert, Kathleen, additional, Upton, Kyle R., additional, Tsai, Yi Ting, additional, Brown, Deborah, additional, Smith, Lee B., additional, Summers, Kim M., additional, Mabbott, Neil A., additional, Piccardo, Pedro, additional, Cheeseman, Michael T., additional, Burdon, Tom, additional, and Hume, David A., additional
- Published
- 2019
- Full Text
- View/download PDF
29. Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus
- Author
-
Pridans, Clare, primary, Raper, Anna, additional, Davis, Gemma M., additional, Alves, Joana, additional, Sauter, Kristin A., additional, Lefevre, Lucas, additional, Regan, Tim, additional, Meek, Stephen, additional, Sutherland, Linda, additional, Thomson, Alison J., additional, Clohisey, Sara, additional, Bush, Stephen J., additional, Rojo, Rocío, additional, Lisowski, Zofia M., additional, Wallace, Robert, additional, Grabert, Kathleen, additional, Upton, Kyle R., additional, Tsai, Yi Ting, additional, Brown, Deborah, additional, Smith, Lee B., additional, Summers, Kim M., additional, Mabbott, Neil A., additional, Piccardo, Pedro, additional, Cheeseman, Michael T., additional, Burdon, Tom, additional, and Hume, David A., additional
- Published
- 2018
- Full Text
- View/download PDF
30. Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB
- Author
-
Owens, Rosie, Grabert, Kathleen, Davies, Claire L., Alfieri, Alessio, Antel, Jack P., Healy, Luke M., and McColl, Barry W.
- Subjects
Cellular and Molecular Neuroscience ,myeloid cells ,TREM2 ,Correction ,microglia ,microglial activation ,NF-κB ,lipopolysaccharide (LPS) ,Original Research ,Neuroscience ,neuroinflammation - Abstract
The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood. We sought to determine how microglial TREM expression is affected under neuroinflammatory conditions in vitro and in vivo. Our data show that microglial Trem1 and Trem2 gene expression are regulated in an opposing manner by lipopolysaccharide (LPS) in vitro in both adult murine and human microglia. LPS caused a significant induction of Trem1 and a contrasting suppression of Trem2 expression. We also observed similar divergent Trem1 and Trem2 responses in vivo in response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in both Trem1 and Trem2 expression in vitro indicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglial Trem1 induction and Trem2 suppression to different Toll-like receptor (TLR) ligands were also evident, notably with Trem1 induction restricted to those ligands activating TLRs signaling via TRIF. Our data show co-ordinated but divergent regulation of microglial TREM receptor expression with a central role for NF-κB. Neuroinflammatory conditions that alter the balance in TREM expression could therefore be an important influence on microglial inflammatory and homeostatic activity with implications for neuroinflammatory and neurodegenerative disease.
- Published
- 2016
31. Corrigendum: Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB
- Author
-
Owens, Rosie, primary, Grabert, Kathleen, additional, Davies, Claire L., additional, Alfieri, Alessio, additional, Antel, Jack P., additional, Healy, Luke M., additional, and McColl, Barry W., additional
- Published
- 2017
- Full Text
- View/download PDF
32. Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB
- Author
-
Owens, Rosie, primary, Grabert, Kathleen, additional, Davies, Claire L., additional, Alfieri, Alessio, additional, Antel, Jack P., additional, Healy, Luke M., additional, and McColl, Barry W., additional
- Published
- 2017
- Full Text
- View/download PDF
33. Defining the Microglia Response during the Time Course of Chronic Neurodegeneration
- Author
-
Vincenti, James E., primary, Murphy, Lita, additional, Grabert, Kathleen, additional, McColl, Barry W., additional, Cancellotti, Enrico, additional, Freeman, Tom C., additional, and Manson, Jean C., additional
- Published
- 2016
- Full Text
- View/download PDF
34. Microglial brain region−dependent diversity and selective regional sensitivities to aging
- Author
-
Grabert, Kathleen, primary, Michoel, Tom, additional, Karavolos, Michail H, additional, Clohisey, Sara, additional, Baillie, J Kenneth, additional, Stevens, Mark P, additional, Freeman, Tom C, additional, Summers, Kim M, additional, and McColl, Barry W, additional
- Published
- 2016
- Full Text
- View/download PDF
35. Csf1r -mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System.
- Author
-
Hawley CA, Rojo R, Raper A, Sauter KA, Lisowski ZM, Grabert K, Bain CC, Davis GM, Louwe PA, Ostrowski MC, Hume DA, Pridans C, and Jenkins SJ
- Subjects
- Animals, Cell Differentiation genetics, Dendritic Cells metabolism, Green Fluorescent Proteins genetics, Macrophage Colony-Stimulating Factor genetics, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia metabolism, Monocytes metabolism, Signal Transduction genetics, Mononuclear Phagocyte System metabolism, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Transgenes genetics
- Abstract
CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r -mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified Δ Csf1- enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r- driven reporter lines, Csf1r -mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double Δ Csf1r -ECFP- Csf1r -mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r- mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines., (Copyright © 2018 The Authors.)
- Published
- 2018
- Full Text
- View/download PDF
36. Microglial brain region-dependent diversity and selective regional sensitivities to aging.
- Author
-
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, and McColl BW
- Subjects
- Aging genetics, Animals, Mice, Phenotype, Transcriptome, Aging physiology, Brain physiology, Microglia physiology
- Abstract
Microglia have critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific, spatially restricted patterns, the origins of which are unknown. We performed to our knowledge the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse, and found that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune-vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during aging. Microglial diversity may enable regionally localized homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.
- Published
- 2016
- Full Text
- View/download PDF
37. Defining the Microglia Response during the Time Course of Chronic Neurodegeneration.
- Author
-
Vincenti JE, Murphy L, Grabert K, McColl BW, Cancellotti E, Freeman TC, and Manson JC
- Subjects
- Animals, Brain pathology, Chronic Disease, Disease Models, Animal, Female, Gene Expression Profiling, Immunohistochemistry, Male, Mice, Inbred BALB C, Microscopy, Inflammation pathology, Microglia physiology, Neurodegenerative Diseases pathology, Prion Diseases pathology
- Abstract
Unlabelled: Inflammation has been proposed as a major component of neurodegenerative diseases, although the precise role it plays has yet to be defined. We examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a prion disease model of chronic neurodegeneration. Initially, we performed an extensive reanalysis of a large study of prion disease, where the transcriptome of mouse brains had been monitored throughout the time course of disease. Our analysis has provided a detailed classification of the disease-associated genes based on cell type of origin and gene function. This revealed that the genes upregulated during disease, regardless of the strain of mouse or prion protein, are expressed predominantly by activated microglia. In order to study the microglia contribution more specifically, we established a mouse model of prion disease in which the 79A murine prion strain was introduced by an intraperitoneal route into BALB/cJ(Fms-EGFP/-) mice, which express enhanced green fluorescent protein under the control of the c-fms operon. Samples were taken at time points during disease progression, and histological analysis of the brain and transcriptional analysis of isolated microglia was carried out. The analysis of isolated microglia revealed a disease-specific, highly proinflammatory signature in addition to an upregulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the importance of microglia within the prion disease process and identifies the nature of the response through gene expression analysis of isolated microglia., Importance: Inflammation has been proposed as a major component of neurodegenerative diseases. We have examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a murine prion disease model of chronic neurodegeneration. Our study demonstrates that genes upregulated throughout the disease process are expressed predominantly by microglia. A disease-specific, highly proinflammatory signature was observed in addition to an upregulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the important contribution of microglia to a chronic neurodegenerative disease process., (Copyright © 2016 Vincenti et al.)
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.