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*

*Corresponding author for this work

Research output: Book/ReportReportAcademicpeer-review

1 Citation (Scopus)
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Abstract

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.

Original languageEnglish
Number of pages17
Volume43
Edition2
DOIs
Publication statusPublished - 27-Feb-2024

Publication series

NameCell reports
PublisherCELL PRESS
ISSN (Print)2211-1247

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