Profiling of microglia in inflammation, aging, and the tumor microenvironment
Author: Friess, Lara
Date: 2022-01-21
Location: CMB lecture hall, Karolinska Institutet, Berzelius väg 21, Solna
Time: 10.00
Department: Institutet för miljömedicin / Institute of Environmental Medicine
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Thesis (856.0Kb)
Abstract
In this thesis I aim to present our ongoing efforts to elucidate activation states and how these are regulated in microglia cells. An extensive body of work is dedicated to understanding how these resident immune cells can acquire certain activation states, as their roles are crucial for a great range of functions in the central nervous system – from homeostasis to pathological occurrences. In summary, the work presented here underlines the importance of microglia cells in the context of inflammation, aging, and the tumor microenvironment.
In project I we identify a possible mechanism of regulation in microglia activation. Under normal circumstances, microglia are highly plastic and respond to a variety of stimuli in their microenvironment by drastically altering their transcriptome. As a result, cells acquire a pro-inflammatory phenotype after exposure to lipopolysaccharides. ATG7, the autophagy-related protein 7, is known to play a vital role in the formation of autophagosomes. Here, we show how the deficiency of Atg7 significantly impacts the ability of microglia to respond to inflammatory stimuli on a transcriptional, as well as on a functional level. This effect was found to be attributed to reduced NF-κB-dependent signaling, which was demonstrated by impaired NF-κB nuclear translocation.
In project II we investigate microglia in the context of the aging brain. Aging is often accompanied by cellular senescence, which can be characterized by growth arrest, a senescence-associated altered secretion of cytokines, mitochondrial dysfunction, and apoptosis resistance. Cells with a senescent phenotype are often associated with areas of age-related pathology, and in aged microglia this can lead to, for example, accumulation of protein aggregates and altered response to neuroinflammatory stimuli. With long-term cultivation of microglia, we show that these cells do not enter age-associated proliferative senescence but present with a distinct transcriptomic state and altered response to inflammatory stimuli.
In project III we show that targeting the H3K27 histone methyltransferase, EZH2, in microglia can affect the invasion and cell death of pediatric glioma. Diffuse midline glioma H3K27M mutant, formerly known as diffuse intrinsic pontine glioma (DIPG), is associated with poor prognosis. This led to studies using EZH2 as a potential therapeutic target. Inhibition of EZH2 in vivo by other groups showed reduced tumor growth and extended survival, however in vitro studies carried out by us, and others, showed limited effects of EZH2 inhibitors on tumor growth and survival. Here, we present that the inhibition of EZH2 in microglia leads to a robust anti-tumoral microglial activation state reducing tumor cell migration and increasing microglia-mediated cell death and phagocytosis of tumor cells, highlighting the tumor microenvironment (TME) as a potential target for further research on glioma treatments.
In project IV we study the interplay of macrophages and microglia in the glioma microenvironment. Infiltrating and resident immune cells in the context of brain tumors are often grouped together as glioma-associated microglia/macrophages (GAMs). In this context, they are known to acquire phenotypes beneficial for tumor growth and progression, which makes them a particularly interesting subject researching treatment targets. Glioblastomas carrying a mutation in an isocitrate dehydrogenase (IDH1) are known to have better clinical prognosis, and less infiltration of GAMs. Here, we show that the presence of macrophages impacts the tumor migration as well as the acquisition of an activated microglia phenotype.
In project I we identify a possible mechanism of regulation in microglia activation. Under normal circumstances, microglia are highly plastic and respond to a variety of stimuli in their microenvironment by drastically altering their transcriptome. As a result, cells acquire a pro-inflammatory phenotype after exposure to lipopolysaccharides. ATG7, the autophagy-related protein 7, is known to play a vital role in the formation of autophagosomes. Here, we show how the deficiency of Atg7 significantly impacts the ability of microglia to respond to inflammatory stimuli on a transcriptional, as well as on a functional level. This effect was found to be attributed to reduced NF-κB-dependent signaling, which was demonstrated by impaired NF-κB nuclear translocation.
In project II we investigate microglia in the context of the aging brain. Aging is often accompanied by cellular senescence, which can be characterized by growth arrest, a senescence-associated altered secretion of cytokines, mitochondrial dysfunction, and apoptosis resistance. Cells with a senescent phenotype are often associated with areas of age-related pathology, and in aged microglia this can lead to, for example, accumulation of protein aggregates and altered response to neuroinflammatory stimuli. With long-term cultivation of microglia, we show that these cells do not enter age-associated proliferative senescence but present with a distinct transcriptomic state and altered response to inflammatory stimuli.
In project III we show that targeting the H3K27 histone methyltransferase, EZH2, in microglia can affect the invasion and cell death of pediatric glioma. Diffuse midline glioma H3K27M mutant, formerly known as diffuse intrinsic pontine glioma (DIPG), is associated with poor prognosis. This led to studies using EZH2 as a potential therapeutic target. Inhibition of EZH2 in vivo by other groups showed reduced tumor growth and extended survival, however in vitro studies carried out by us, and others, showed limited effects of EZH2 inhibitors on tumor growth and survival. Here, we present that the inhibition of EZH2 in microglia leads to a robust anti-tumoral microglial activation state reducing tumor cell migration and increasing microglia-mediated cell death and phagocytosis of tumor cells, highlighting the tumor microenvironment (TME) as a potential target for further research on glioma treatments.
In project IV we study the interplay of macrophages and microglia in the glioma microenvironment. Infiltrating and resident immune cells in the context of brain tumors are often grouped together as glioma-associated microglia/macrophages (GAMs). In this context, they are known to acquire phenotypes beneficial for tumor growth and progression, which makes them a particularly interesting subject researching treatment targets. Glioblastomas carrying a mutation in an isocitrate dehydrogenase (IDH1) are known to have better clinical prognosis, and less infiltration of GAMs. Here, we show that the presence of macrophages impacts the tumor migration as well as the acquisition of an activated microglia phenotype.
List of papers:
I. Lara Friess, Mathilde Cheray, Lily Keane, Kathleen Grabert and Bertrand Joseph. (2021). Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response. Mol Brain. 14(1):87.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Martin Skandik, Lara Friess, Lily Keane, Kathleen Grabert, Mireia Cruz de Los Santos and Bertrand Joseph. Aged microglia: development of immunosenescence without replicative senescence. [Manuscript]
III. Lily Keane, Mathilde Cheray, Dalel Saidi, Caoimhe Kirby, Lara Friess, Patricia Gonzalez-Rodriguez, Maren Elisabeth Gerdes, Kathleen Grabert, Barry W McColl and Bertrand Joseph. (2021). Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas. Neuro-Oncology Advances. Volume 3, Issue 1, January-December 2021, vdab096.
Fulltext (DOI)
Pubmed
IV. Lara Friess, Lily Keane, Mercedes Posada-Pérez and Bertrand Joseph. Understanding if the presence of peripheral macrophages in the context of glioblastoma influences the tumor-associated microglial phenotype. [Manuscript]
I. Lara Friess, Mathilde Cheray, Lily Keane, Kathleen Grabert and Bertrand Joseph. (2021). Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response. Mol Brain. 14(1):87.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Martin Skandik, Lara Friess, Lily Keane, Kathleen Grabert, Mireia Cruz de Los Santos and Bertrand Joseph. Aged microglia: development of immunosenescence without replicative senescence. [Manuscript]
III. Lily Keane, Mathilde Cheray, Dalel Saidi, Caoimhe Kirby, Lara Friess, Patricia Gonzalez-Rodriguez, Maren Elisabeth Gerdes, Kathleen Grabert, Barry W McColl and Bertrand Joseph. (2021). Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas. Neuro-Oncology Advances. Volume 3, Issue 1, January-December 2021, vdab096.
Fulltext (DOI)
Pubmed
IV. Lara Friess, Lily Keane, Mercedes Posada-Pérez and Bertrand Joseph. Understanding if the presence of peripheral macrophages in the context of glioblastoma influences the tumor-associated microglial phenotype. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Joseph, Bertrand
Co-supervisor: Blomgren, Klas
Issue date: 2021-12-10
Rights:
Publication year: 2021
ISBN: 978-91-8016-399-6
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