Microglia : guardians across the lifespan and disease spectrum
Author: Vázquez Cabrera, Guillermo
Date: 2024-09-20
Location: Eva & Georg Klein, Solnavägen 9, Biomedicum, Karolinska Institutet, Solna
Time: 09.30
Department: Institutet för miljömedicin / Institute of Environmental Medicine
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Thesis (2.732Mb)
Abstract
Microglia, the resident immune cells of the central nervous system, are crucial for maintaining homeostasis and responding to injury and disease. In this thesis, I aim to elucidate the molecular diversity and regulatory mechanisms governing microglia phenotype acquisition. The studies highlight microglia's roles in development, aging, and brain tumour context, underscoring the potential for therapeutic interventions targeting microglia-specific pathways.
Paper I: ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. In the first project, we describe a newly identified subtype of microglia expressing the metabolic enzyme arginase-1 (ARG1), predominantly located in the basal forebrain and ventral striatum during early postnatal development. These ARG1+ microglia are integral to neurodevelopment, as their knockdown leads to impaired cholinergic innervation and dendritic spine maturation, culminating in cognitive deficits. This discovery enhances our understanding of microglial diversity and provides a foundation for future research into microglia subtype-specific functions.
Paper II: Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions. The second project examines the aging process in microglia, focusing on their phenotype acquisition. Long-term cultivation of BV2 microglia revealed that aged microglia exhibit a distinct gene expression profile and a downregulated response to pro-inflammatory stimuli. Comparative analysis with datasets from aged mice and humans identified a conserved aging signature, Specifically the upregulation of the lactate pump MCT4 and downregulation of the homeostatic marker P2RY12 that work as sensing protein. This study underscores the importance of these molecular determinants in microglial aging, providing insights for potential interventions to reprogram aged microglia and help treat age-related neurological disorders.
Paper III: ID2-ETS2 axis regulates the transcriptional acquisition of protumoral microglia phenotype in glioma. The third project explores the mechanisms through which glioma cells reprogram microglia into a tumour-supportive state. Our research identifies a molecular axis in microglia that involves the co-regulator of transcription factors, inhibitor of DNA binding 2 (ID2), and the transcription factor ETS proto-oncogene 2 (ETS2). This axis, activated in microglia exposed to glioma cells, appears to drive the reprogramming process. Notably, this molecular pathway was also active in microglia from human glioblastoma biopsies, underscoring its potential as a therapeutic target for modulating microglial functions to inhibit glioma progression.
Paper IV: Glioma-induced DNMT3A-dependent reduction of DNA methylation in microglia promotes a transient anti-tumoral phenotype. The fourth project hypothesizes that microglia, upon stimulation by glioma cells, may transit through a reactive state characterized by increased inflammatory and immunogenic properties before acquiring a tumour-supportive phenotype. This state is marked by reduced DNMT3A chromatin occupancy and DNA demethylation, promoting pro-inflammatory gene expression. This intermediate state could offer a novel therapeutic angle for glioma treatment by leveraging the microglial response before it becomes tumour-supportive.
Paper I: ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. In the first project, we describe a newly identified subtype of microglia expressing the metabolic enzyme arginase-1 (ARG1), predominantly located in the basal forebrain and ventral striatum during early postnatal development. These ARG1+ microglia are integral to neurodevelopment, as their knockdown leads to impaired cholinergic innervation and dendritic spine maturation, culminating in cognitive deficits. This discovery enhances our understanding of microglial diversity and provides a foundation for future research into microglia subtype-specific functions.
Paper II: Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions. The second project examines the aging process in microglia, focusing on their phenotype acquisition. Long-term cultivation of BV2 microglia revealed that aged microglia exhibit a distinct gene expression profile and a downregulated response to pro-inflammatory stimuli. Comparative analysis with datasets from aged mice and humans identified a conserved aging signature, Specifically the upregulation of the lactate pump MCT4 and downregulation of the homeostatic marker P2RY12 that work as sensing protein. This study underscores the importance of these molecular determinants in microglial aging, providing insights for potential interventions to reprogram aged microglia and help treat age-related neurological disorders.
Paper III: ID2-ETS2 axis regulates the transcriptional acquisition of protumoral microglia phenotype in glioma. The third project explores the mechanisms through which glioma cells reprogram microglia into a tumour-supportive state. Our research identifies a molecular axis in microglia that involves the co-regulator of transcription factors, inhibitor of DNA binding 2 (ID2), and the transcription factor ETS proto-oncogene 2 (ETS2). This axis, activated in microglia exposed to glioma cells, appears to drive the reprogramming process. Notably, this molecular pathway was also active in microglia from human glioblastoma biopsies, underscoring its potential as a therapeutic target for modulating microglial functions to inhibit glioma progression.
Paper IV: Glioma-induced DNMT3A-dependent reduction of DNA methylation in microglia promotes a transient anti-tumoral phenotype. The fourth project hypothesizes that microglia, upon stimulation by glioma cells, may transit through a reactive state characterized by increased inflammatory and immunogenic properties before acquiring a tumour-supportive phenotype. This state is marked by reduced DNMT3A chromatin occupancy and DNA demethylation, promoting pro-inflammatory gene expression. This intermediate state could offer a novel therapeutic angle for glioma treatment by leveraging the microglial response before it becomes tumour-supportive.
List of papers:
I. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Vassilis Stratoulias, Rocío Ruiz, Shigeaki Kanatani, Ahmed M. Osman, Lily Keane, Jose A. Armengol, Antonio Rodríguez-Moreno, Adriana-Natalia Murgoci, Irene García-Domínguez, Isabel Alonso-Bellido, Fernando González Ibáñez, Katherine Picard, Guillermo Vázquez-Cabrera, Mercedes Posada-Pérez, Nathalie Vernoux, Dario Tejera, Kathleen Grabert, Mathilde Cheray, Patricia González-Rodríguez, Eva M. Pérez-Villegas, Irene Martínez-Gallego, Alejandro Lastra-Romero, David Brodin, Javier AvilaCariño, Yang Cao, Mikko Airavaara, Per Uhlén, Michael T. Heneka, Marie-Ève Tremblay, Klas Blomgren, Jose L. Venero & Bertrand Joseph. Nat Neurosci. 2023 Jun;26(6):1008-1020.
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II. Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions. Martin Skandik, Lara Friess, Guillermo Vázquez-Cabrera, Lily Keane, Kathleen Grabert, Mireia Cruz De los Santos, Mercedes Posada Perez, Austeja Baleviciute, Mathilde Cheray and Bertrand Joseph. [Manuscript]
III. ID2-ETS2 axis regulates the transcriptional acquisition of protumoral microglia phenotype in glioma. Guillermo Vázquez-Cabrera, Martin Škandík, Noémie Roncier, Farah Real Oualit, Mireia Cruz De Los Santos, Austeja Baleviciute, Mathilde Cheray and Bertrand Joseph. Cell Death Dis. 2024 Jul ;15(7):512.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Glioma-induced DNMT3A-dependent reduction of DNA methylation in microglia promotes a transient anti-tumoral phenotype. Mathilde Cheray, Adriana-Natalia Murgoci, Adamantia Fragkopoulou, Carlos F.D. Rodrigues, Ahmed M. Osman, Christine Hong, Guillermo Vázquez-Cabrera, Lara Friess, Lena-Maria Carlson, Shigeaki Kanatani, Yue Li, Anastasius Damdimopoulos, Per Uhlén, Fredrik Kamme, Klas Blomgren, and Bertrand Joseph. [Manuscript]
I. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Vassilis Stratoulias, Rocío Ruiz, Shigeaki Kanatani, Ahmed M. Osman, Lily Keane, Jose A. Armengol, Antonio Rodríguez-Moreno, Adriana-Natalia Murgoci, Irene García-Domínguez, Isabel Alonso-Bellido, Fernando González Ibáñez, Katherine Picard, Guillermo Vázquez-Cabrera, Mercedes Posada-Pérez, Nathalie Vernoux, Dario Tejera, Kathleen Grabert, Mathilde Cheray, Patricia González-Rodríguez, Eva M. Pérez-Villegas, Irene Martínez-Gallego, Alejandro Lastra-Romero, David Brodin, Javier AvilaCariño, Yang Cao, Mikko Airavaara, Per Uhlén, Michael T. Heneka, Marie-Ève Tremblay, Klas Blomgren, Jose L. Venero & Bertrand Joseph. Nat Neurosci. 2023 Jun;26(6):1008-1020.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions. Martin Skandik, Lara Friess, Guillermo Vázquez-Cabrera, Lily Keane, Kathleen Grabert, Mireia Cruz De los Santos, Mercedes Posada Perez, Austeja Baleviciute, Mathilde Cheray and Bertrand Joseph. [Manuscript]
III. ID2-ETS2 axis regulates the transcriptional acquisition of protumoral microglia phenotype in glioma. Guillermo Vázquez-Cabrera, Martin Škandík, Noémie Roncier, Farah Real Oualit, Mireia Cruz De Los Santos, Austeja Baleviciute, Mathilde Cheray and Bertrand Joseph. Cell Death Dis. 2024 Jul ;15(7):512.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Glioma-induced DNMT3A-dependent reduction of DNA methylation in microglia promotes a transient anti-tumoral phenotype. Mathilde Cheray, Adriana-Natalia Murgoci, Adamantia Fragkopoulou, Carlos F.D. Rodrigues, Ahmed M. Osman, Christine Hong, Guillermo Vázquez-Cabrera, Lara Friess, Lena-Maria Carlson, Shigeaki Kanatani, Yue Li, Anastasius Damdimopoulos, Per Uhlén, Fredrik Kamme, Klas Blomgren, and Bertrand Joseph. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Joseph, Bertrand
Co-supervisor: Cheray, Mathilde; Osman, Ahmed
Issue date: 2024-08-23
Rights:
Publication year: 2024
ISBN: 978-91-8017-722-1
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