Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state

Daniëlle C. Voshart; Takuya Oshima; Yuting Jiang; Gideon P. van der Linden; Anna P. Ainslie; Luiza Reali Nazario; Fleur van Buuren-Broek; Ayla C. Scholma; Hilmar R.J. van Weering; Nieske Brouwer; Jeffrey Sewdihal; Uilke Brouwer; Rob P. Coppes; Inge R. Holtman; Bart J.L. Eggen; Susanne M. Kooistra; Lara Barazzuol

Cell Reports (Feb 2024)

Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state

Daniëlle C. Voshart,
Takuya Oshima,
Yuting Jiang,
Gideon P. van der Linden,
Anna P. Ainslie,
Luiza Reali Nazario,
Fleur van Buuren-Broek,
Ayla C. Scholma,
Hilmar R.J. van Weering,
Nieske Brouwer,
Jeffrey Sewdihal,
Uilke Brouwer,
Rob P. Coppes,
Inge R. Holtman,
Bart J.L. Eggen,
Susanne M. Kooistra,
Lara Barazzuol

Affiliations

Daniëlle C. Voshart: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Takuya Oshima: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Yuting Jiang: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Gideon P. van der Linden: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Anna P. Ainslie: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Luiza Reali Nazario: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Fleur van Buuren-Broek: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Ayla C. Scholma: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Hilmar R.J. van Weering: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Nieske Brouwer: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Jeffrey Sewdihal: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Uilke Brouwer: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Rob P. Coppes: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Inge R. Holtman: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Bart J.L. Eggen: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Susanne M. Kooistra: Department of Biomedical Sciences, Section of Molecular Neurobiology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands
Lara Barazzuol: Department of Biomedical Sciences, Section of Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; Corresponding author

Journal volume & issue: Vol. 43, no. 2
p. 113764

Abstract

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Summary: Over half of patients with brain tumors experience debilitating and often progressive cognitive decline after radiotherapy treatment. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults, microglia can develop innate immune memory (IIM), which can either enhance (priming or training) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigate whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats show a stronger immune response to a secondary inflammatory insult, demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of postmortem normal-appearing non-tumor brain tissue of patients with glioblastoma indicates that radiation-induced microglial priming is likely conserved in humans. Targeting microglial priming or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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