Microglia : guardians across the lifespan and disease spectrum

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.

List of scientific papers

I. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Vassilis Stratoulias, Roc’o Ruiz, Shigeaki Kanatani, Ahmed M. Osman, Lily Keane, Jose A. Armengol, Antonio Rodr’guez-Moreno, Adriana-Natalia Murgoci, Irene Garc’a-Dom’nguez, Isabel Alonso-Bellido, Fernando Gonz‡lez Ib‡–ez, Katherine Picard, Guillermo V‡zquez-Cabrera, Mercedes Posada-PŽrez, Nathalie Vernoux, Dario Tejera, Kathleen Grabert, Mathilde Cheray, Patricia Gonz‡lez-Rodr’guez, Eva M. PŽrez-Villegas, Irene Mart’nez-Gallego, Alejandro Lastra-Romero, David Brodin, Javier AvilaCari–o, Yang Cao, Mikko Airavaara, Per UhlŽn, Michael T. Heneka, Marie-éve Tremblay, Klas Blomgren, Jose L. Venero & Bertrand Joseph. Nat Neurosci. 2023 Jun;26(6):1008-1020.
https://doi.org/10.1038/s41593-023-01326-3

II. Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions. Martin Skandik, Lara Friess, Guillermo V‡zquez-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 V‡zquez-Cabrera, Martin _kand’k, NoŽmie Roncier, Farah Real Oualit, Mireia Cruz De Los Santos, Austeja Baleviciute, Mathilde Cheray and Bertrand Joseph. Cell Death Dis. 2024 Jul ;15(7):512.
https://doi.org/10.1038/s41419-024-06903-3

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 V‡zquez-Cabrera, Lara Friess, Lena-Maria Carlson, Shigeaki Kanatani, Yue Li, Anastasius Damdimopoulos, Per UhlŽn, Fredrik Kamme, Klas Blomgren, and Bertrand Joseph. [Manuscript]