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ORIGINAL RESEARCH article

Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
Volume 18 - 2024 | doi: 10.3389/fncel.2024.1440559
This article is part of the Research Topic 15 Years of Frontiers in Cellular Neuroscience: The Dual Role of Microglia in (Neuro)inflammation View all 4 articles

Fractionated alpha and mixed beam radiation promote stronger proinflammatory effects compared to acute exposure and trigger phagocytosis

Provisionally accepted
Mostafa Karimi Roshan Mostafa Karimi Roshan 1Sergey Belikov Sergey Belikov 1Melissa Ix Melissa Ix 2Nicoletta Protti Nicoletta Protti 3Claudia Balducci Claudia Balducci 4Richard Dodel Richard Dodel 2J Alexander Ross J Alexander Ross 2Lovisa Lundholm Lovisa Lundholm 1*
  • 1 Stockholm University, Stockholm, Sweden
  • 2 University of Duisburg-Essen, Duisburg, North Rhine-Westphalia, Germany
  • 3 University of Pavia, Pavia, Lombardy, Italy
  • 4 Department of Neuroscience, Mario Negri Pharmacological Research Institute (IRCCS), Milano, Lombardy, Italy

The final, formatted version of the article will be published soon.

    Aiming to evaluate safety aspects of a recently proposed approach to target Alzheimer's disease, we mimicked a complex boron neutron capture therapy field using a mixed beam consisting of high-and low-linear energy transfer (LET) radiation, 241 Am alpha particles (α) and/or X-ray radiation respectively, in human microglial (HMC3) cells. Acute exposure to 2 Gy X-rays induced the strongest response in the formation of γH2AX foci 30 min post irradiation, while αand mixed beaminduced damage (α:X-ray = 3:1) sustained longer. Fractionation of the same total dose (0.4 Gy daily) induced a similar number of γH2AX foci as after acute radiation, however, αor mixed irradiation caused a higher expression of DNA damage response genes CDKN1A and MDM2 24 hrs after the last fraction, as well as a stronger decrease in cell viability and clonogenic survival compared to acute exposure. Phosphorylation of STING, followed by phosphorylation of NF-κB subunit p65, was rapidly induced (1 or 3 h, respectively) after the last fraction by all radiation qualities. This led to IL-1β secretion into the medium, strongly elevated expression of pro-inflammatory cytokine genes and enhanced phagocytosis after fractionated exposure to αand mixed beam-irradiation compared to their acute counterparts 24 hrs post-irradiation. Nevertheless, all inflammatory changes were returning to basal levels or below 10-14 days post irradiation. In conclusion, we demonstrate strong transient pro-inflammatory induction by daily high-LET radiation in a microglia model, triggering phagocytosis which may aid in clearing amyloid beta, but importantly, from a safety perspective, without long-term alterations.

    Keywords: Radiation, Microglia, Inflammation, DNA Damage, cGAS-STING, Phagocytosis

    Received: 29 May 2024; Accepted: 07 Nov 2024.

    Copyright: © 2024 Karimi Roshan, Belikov, Ix, Protti, Balducci, Dodel, Ross and Lundholm. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Lovisa Lundholm, Stockholm University, Stockholm, Sweden

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