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Open AccessArticle

Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion

1
Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden
2
Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, S-171 76 Stockholm, Sweden
3
Pediatric Oncology, Karolinska University Hospital, S-171 76 Stockholm, Sweden
4
Department of Physiology and Pharmacology, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8603; https://doi.org/10.3390/ijms21228603
Received: 21 October 2020 / Revised: 9 November 2020 / Accepted: 10 November 2020 / Published: 15 November 2020
(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)
Microglia, predominant parenchymal resident macrophages in the central nervous system (CNS), are crucial players in neurodevelopment and CNS homeostasis. In disease conditions, pro-inflammatory microglia predominate over their regulatory counterparts, and are thus a potential immunotherapeutic target. It has been well documented that microglia can be effectively depleted using both conditional genetic Cx3cr1Cre-diphtheria toxin receptor (DTR)/diphtheria toxin subunit A (DTA) animal models and pharmacological colony-stimulating factor 1 receptor (CSF1R) inhibitors. Recent advances using these approaches have expanded our knowledge of the multitude of tasks conducted by microglia in both homeostasis and diseases. Importantly, experimental microglial depletion has been proven to exert neuroprotective effects in an increasing number of disease models, mostly explained by reduced neuroinflammation. However, the comprehensive effects of additional targets such as circulating monocytes and peripheral tissue macrophages during microglial depletion periods have not been investigated widely, and for those studies addressing the issue the conclusions are mixed. In this study, we demonstrate that experimental microglial depletion using both Cx3cr1CreER/+Rosa26DTA/+ mice and different doses of CSF1R inhibitor PLX3397 exert crucial influences on circulating monocytes and peripheral tissue macrophages. Our results suggest that effects on peripheral immunity should be considered both in interpretation of microglial depletion studies, and especially in the potential translation of microglial depletion and replacement therapies. View Full-Text
Keywords: monocytes; tissue macrophages; colony-stimulating factor 1 receptor inhibitor monocytes; tissue macrophages; colony-stimulating factor 1 receptor inhibitor
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MDPI and ACS Style

Han, J.; Fan, Y.; Zhou, K.; Zhu, K.; Blomgren, K.; Lund, H.; Zhang, X.-M.; Harris, R.A. Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion. Int. J. Mol. Sci. 2020, 21, 8603. https://doi.org/10.3390/ijms21228603

AMA Style

Han J, Fan Y, Zhou K, Zhu K, Blomgren K, Lund H, Zhang X-M, Harris RA. Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion. International Journal of Molecular Sciences. 2020; 21(22):8603. https://doi.org/10.3390/ijms21228603

Chicago/Turabian Style

Han, Jinming; Fan, Yueshan; Zhou, Kai; Zhu, Keying; Blomgren, Klas; Lund, Harald; Zhang, Xing-Mei; Harris, Robert A. 2020. "Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion" Int. J. Mol. Sci. 21, no. 22: 8603. https://doi.org/10.3390/ijms21228603

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