CSF1 receptor signaling is necessary for microglia viability, which unmasks a cell that rapidly repopulates the microglia-depleted adult brain

By M. Elmore, A. Najafi, Maya A. Koike, N. Dagher, Elizabeth E. Spangenberg, Rachel A. Rice, M. Kitazawa, Bernice Matusow, Hoa T. Nguyen, B. West and 1 more. Neuron, 2014

1,658 citations recorded by the source corpus.

The colony stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microgliain the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ~99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within one week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin positive cells that then differentiate into microglia.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/cb5426eabb67f863ef5735ee4d6bffb118ed9172

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. M. Guilliams
2. A. Mildner
3. R. Ransohoff
4. Steffen Jung
5. Florent Ginhoux
6. C. Varol
7. O. Butovsky
8. Beth Stevens

In Neurology

1. R. Ransohoff
2. Beth Stevens
3. Alok Kumar
4. Chao Gao
5. Shengdi Chen
6. Yuyan Tan
7. Jingwen Jiang
8. O. Butovsky

Citations in the corpus

• Neuroinflammation: The Devil is in the Details (2016, positive): “Nonetheless, when depleted, microglia turnover is possible from a potential progenitor source within the CNS (Elmore et al. 2014).”
• Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options (2020, background): “PLX3397 and similar CSF1R inhibitors have been shown to deplete brain microglia at high doses (Elmore et al., 2014).”
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “Mature microglia also require CSF1R signaling, as demonstrated by the significant loss of microglia in adult mice treated with Csf-1R inhibitors.(69) CSF1R ligands are major components in all protocols for generating induced pluripotent stem cell (iPSC)-derived microglia, underscoring that CSF1R sig”
• Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain (2017, methodology): “…shown to cause blockade of microglial proliferation, but not microglia survival (Gómez-Nicola et al., 2013; Uitdehaag et al., 2011; De Lucia et al., 2016; Olmos-Alonso et al., 2016), in contrast to the microglia-depleting effects caused by the CSF1R inhibitor PLX3397 (Elmore et al., 2014).”
• Developmental and Functional Heterogeneity of Monocytes. (2018, background): “Interestingly, the lifespan of Ly6CLow monocytes can be extended to up to 2 weeks, which is likely dependent upon the availability of CSF1 (Yona et al., 2013), a critical factor controlling monocyte/macrophage maintenance (Bartocci et al., 1987; Elmore et al., 2014).”
• An environment-dependent transcriptional network specifies human microglia identity (2017, background): “Microglia share many traits with other subsets of tissue-resident macrophages, including dependence on the CSF1 receptor for differentiation and survival (18, 20), a requirement for PU.”
• Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes (2018, background): “Rapid expansion of microglia also occurs in response to injury or disease, and their self-renewal capacity is sufficient to replenish the population within days following depletion of all but 1%–2% of microglia (Elmore et al., 2014).”
• The microenvironmental landscape of brain tumors (2017, background): “Therefore, the maintenance of microglia in the normal adult brain is thought to occur through prolonged cellular longevity and local proliferation (Ajami et al., 2007; Elmore et al., 2014; Gomez Perdiguero et al., 2015).”
• Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017, methodology): “targeting CSF1R have been extensively used to understand microglial function in AD (6, 191).”