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Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging
Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition–induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time (to our knowled...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society of Nuclear Medicine
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454465/ https://www.ncbi.nlm.nih.gov/pubmed/35115368 http://dx.doi.org/10.2967/jnumed.121.263004 |
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author | Barca, Cristina Kiliaan, Amanda J. Wachsmuth, Lydia Foray, Claudia Hermann, Sven Faber, Cornelius Schäfers, Michael Wiesmann, Maximilian Zinnhardt, Bastian Jacobs, Andreas H. |
author_facet | Barca, Cristina Kiliaan, Amanda J. Wachsmuth, Lydia Foray, Claudia Hermann, Sven Faber, Cornelius Schäfers, Michael Wiesmann, Maximilian Zinnhardt, Bastian Jacobs, Andreas H. |
author_sort | Barca, Cristina |
collection | PubMed |
description | Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition–induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time (to our knowledge) the effects of microglia repopulation on inflammation and functional outcomes in an ischemic mouse model using translocator protein (TSPO)-PET/CT and MR imaging, ex vivo characterization, and behavioral tests. Methods: Eight C57BL/6 mice per group underwent a 30-min transient occlusion of the middle cerebral artery. The treatment group received CSF-1R inhibitor in 1,200 ppm PLX5622 chow (Plexxikon Inc.) from days 3 to 7 to induce microglia/macrophage depletion and then went back to a control diet to allow repopulation. The mice underwent T2-weighted MRI on day 1 after ischemia and (18)F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ((18)F-DPA-714) (TSPO) PET/CT on days 7, 14, 21, and 30. The percentage injected tracer dose per milliliter within the infarct, contralateral striatum, and spleen was assessed. Behavioral tests were performed to assess motor function recovery. Brains were harvested on days 14 and 35 after ischemia for ex vivo analyses (immunoreactivity and real-time quantitative polymerase chain reaction) of microglia- and macrophage-related markers. Results: Repopulation significantly increased (18)F-DPA-714 uptake within the infarct on days 14 (P < 0.001) and 21 (P = 0.002) after ischemia. On day 14, the ionized calcium binding adaptor molecule 1 (Iba-1)–positive cell population showed significantly higher expression of TSPO, CSF-1R, and CD68, in line with microglia repopulation. Gene expression analyses on day 14 indicated a significant increase in microglia-related markers (csf-1r, aif1, and p2ry12) with repopulation, whereas peripheral cell recruitment–related gene expression decreased (cx3cr1 and ccr2), indicative of peripheral recruitment during CSF-1R inhibition. Similarly, uncorrected spleen uptake was significantly higher on day 7 after ischemia with treatment (P = 0.001) and decreased after drug withdrawal. PLX5622-treated mice walked a longer distance (P < 0.001) and more quickly (P = 0.009), and showed greater forelimb strength (P < 0.001), than control mice on day 14. Conclusion: This study highlighted the potential of (18)F-DPA-714 PET/CT imaging to track microglia and macrophage repopulation after short-term CSF-1R inhibition in stroke. |
format | Online Article Text |
id | pubmed-9454465 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Society of Nuclear Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-94544652023-03-01 Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging Barca, Cristina Kiliaan, Amanda J. Wachsmuth, Lydia Foray, Claudia Hermann, Sven Faber, Cornelius Schäfers, Michael Wiesmann, Maximilian Zinnhardt, Bastian Jacobs, Andreas H. J Nucl Med Basic Science Investigation Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition–induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time (to our knowledge) the effects of microglia repopulation on inflammation and functional outcomes in an ischemic mouse model using translocator protein (TSPO)-PET/CT and MR imaging, ex vivo characterization, and behavioral tests. Methods: Eight C57BL/6 mice per group underwent a 30-min transient occlusion of the middle cerebral artery. The treatment group received CSF-1R inhibitor in 1,200 ppm PLX5622 chow (Plexxikon Inc.) from days 3 to 7 to induce microglia/macrophage depletion and then went back to a control diet to allow repopulation. The mice underwent T2-weighted MRI on day 1 after ischemia and (18)F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ((18)F-DPA-714) (TSPO) PET/CT on days 7, 14, 21, and 30. The percentage injected tracer dose per milliliter within the infarct, contralateral striatum, and spleen was assessed. Behavioral tests were performed to assess motor function recovery. Brains were harvested on days 14 and 35 after ischemia for ex vivo analyses (immunoreactivity and real-time quantitative polymerase chain reaction) of microglia- and macrophage-related markers. Results: Repopulation significantly increased (18)F-DPA-714 uptake within the infarct on days 14 (P < 0.001) and 21 (P = 0.002) after ischemia. On day 14, the ionized calcium binding adaptor molecule 1 (Iba-1)–positive cell population showed significantly higher expression of TSPO, CSF-1R, and CD68, in line with microglia repopulation. Gene expression analyses on day 14 indicated a significant increase in microglia-related markers (csf-1r, aif1, and p2ry12) with repopulation, whereas peripheral cell recruitment–related gene expression decreased (cx3cr1 and ccr2), indicative of peripheral recruitment during CSF-1R inhibition. Similarly, uncorrected spleen uptake was significantly higher on day 7 after ischemia with treatment (P = 0.001) and decreased after drug withdrawal. PLX5622-treated mice walked a longer distance (P < 0.001) and more quickly (P = 0.009), and showed greater forelimb strength (P < 0.001), than control mice on day 14. Conclusion: This study highlighted the potential of (18)F-DPA-714 PET/CT imaging to track microglia and macrophage repopulation after short-term CSF-1R inhibition in stroke. Society of Nuclear Medicine 2022-09 /pmc/articles/PMC9454465/ /pubmed/35115368 http://dx.doi.org/10.2967/jnumed.121.263004 Text en © 2022 by the Society of Nuclear Medicine and Molecular Imaging. https://creativecommons.org/licenses/by/4.0/Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml. |
spellingShingle | Basic Science Investigation Barca, Cristina Kiliaan, Amanda J. Wachsmuth, Lydia Foray, Claudia Hermann, Sven Faber, Cornelius Schäfers, Michael Wiesmann, Maximilian Zinnhardt, Bastian Jacobs, Andreas H. Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title | Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title_full | Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title_fullStr | Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title_full_unstemmed | Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title_short | Short-Term Colony-Stimulating Factor 1 Receptor Inhibition–Induced Repopulation After Stroke Assessed by Longitudinal (18)F-DPA-714 PET Imaging |
title_sort | short-term colony-stimulating factor 1 receptor inhibition–induced repopulation after stroke assessed by longitudinal (18)f-dpa-714 pet imaging |
topic | Basic Science Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454465/ https://www.ncbi.nlm.nih.gov/pubmed/35115368 http://dx.doi.org/10.2967/jnumed.121.263004 |
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