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
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.
