Deciphering microglia plasticity in glioma
Microglia are the innate immune cells of the brain. One of the main characteristics of microglia is its extremely plasticity, which is necessary for them to deal with changing circumstances. Activation of microglia can contribute to contrasting effects by either proinflammatory, anti-inflammatory, or tumor-supportive phenotypes. Adult and pediatric high-grade glioma are very aggressive tumors with a median survival of less than a year. The pathological hallmark of these tumors is the invasion into brain tissue, which contributes significantly to the failure of current therapeutic treatments. Glioma cancer recruits microglia for their expansion and invasiveness. During the course of the disease, glioma-infiltrating microglia undergo cellular reprogramming and functional changes that are controlled by specific intracellular signaling pathways and epigenetic mechanisms.
In the first study, we describe a novel epigenetic pathway associated with microglia reprogramming toward the tumor-supporting phenotype that is of benefit to glioma biology. We demonstrate that the glioma-induced microglia tumor-supporting phenotype is coupled with a functional interaction between sirtuin 1 (SIRT1) and the specific H4K16 histone acetyltransferase hMOF, which leads to an increase of the global histone 4 lysine 16 (H4K16) acetylation. During the process of microglia reprogramming toward the tumor-supporting phenotype, we show that SIRT1 deacetylates hMOF that promotes its recruitment to the chromatin and enhances its enzymatic activity against H4K16 acetylation. The high enrichment in H4K16 acetylation results in an aberrant gene expression in tumor-supporting microglia. Furthermore, we show that the manipulation of H4K16’s acetylation level, controlled by the enzymes hMOF and SIRT1, has an impact on microglial pro-tumoral activation.
Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGGs) that carries H3K27M mutation and has a reduced global level of the repressive posttranslational histone modification H3K27me3. In the second study, we explore the microglia profile in pHGGs and DIPG. Our research work suggests that microglia activation towards a tumorsupporting phenotype exhibits a significantly decreased level of H3K27me3 and demethylase JMJD3. Interestingly, the inhibition of EZH2 or JMJD3/UTX enzymes reduces the switch of microglia into pro-tumoral phenotype, which in turn has a negative effect on DIPG and pHGGS invasion.
In the third study, we thoroughly describe a completely novel molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype. We demonstrate in vitro and in vivo that decreased basal caspase-3 activity in microglia is a necessary condition for their polarization into a tumor-supportive phenotype. We reveal that nitric oxide originating from the glioma’s nitric oxide synthase-2 induces the inhibition of microglial thioredoxin-2 denitrosylation activity, which in turn leads to an increased S-nitrosylation of caspase-3.
List of scientific papers
I. Glioma-induced SIRT1-dependent activation of hMOF histone H4 lysine 16 acetyltransferase in microglia promotes a tumor-supporting phenotype. Dalel Saidi, Mathilde Cheray, Ahmed M. Osman, Vassilis Stratoulias, Olle R. Lindberg, Xianli Shen, Klas Blomgren, and Bertrand Joseph. Oncoimmunology. 2018; V7(2): e1382790.
https://doi.org/10.1080/2162402X.2017.1382790
II. Inhibition of EZH2 or JMJD3 reduces microglial pro-tumoral activation in Diffuse Intrinsic Pontine Glioma. Dalel Saidi, Lara Friess, Bertrand Joseph. [Manuscript]
III. Glioma-induced inhibition of caspase-3 in microglia promotes a tumorsupportive phenotype. Shen X, Burguillos MA, Osman AM, Frijhoff J, Carrillo-Jiménez A, Kanatani S, Augsten M, Saidi D, Rodhe J, Kavanagh E, Rongvaux A, Rraklli V, Nyman U, Holmberg J, Östman A, Flavell RA, Barragan A, Venero JL, Blomgren K, Joseph B. Nature Immunology. 2016, 17(11):1282-1290.
https://doi.org/10.1038/ni.3545
History
Defence date
2019-02-01Department
- Institute of Environmental Medicine
Publisher/Institution
Karolinska InstitutetMain supervisor
Joseph, BertrandCo-supervisors
Hermanson, Ola; Heldring, NinaPublication year
2019Thesis type
- Doctoral thesis
ISBN
978-91-7831-322-8Number of supporting papers
3Language
- eng