The transcription factor PU.1 is critical for viability and function of human brain microglia

Smith, Amy M.; Gibbons, Hannah M.; Oldfield, Robyn L.; Bergin, Peter M.; Mee, Edward W.; Faull, Richard L. M.; Dragunow, Mike

doi:10.1002/glia.22486

Cited by 144Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesPhagocytosis and Immune Regulation

The transcription factor PU.1 is critical for viability and function of human brain microglia

Smith, Amy M., Gibbons, Hannah M., Oldfield, Robyn L., Bergin, Peter M., Mee, Edward W., Faull, Richard L. M., Dragunow, Mike·2013·Glia

DOI 10.1002/glia.22486

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Abstract

Microglia are the predominant resident immune cells of the brain and can assume a range of phenotypes. They are critical for normal brain development and function but can also contribute to many disease processes. Although they are widely studied, the transcriptional control of microglial phenotype and activation requires further research. PU.1 is a key myeloid transcription factor expressed by peripheral macrophages and rodent microglia. In this article, we report the presence of PU.1 specifically in microglia of the adult human brain and we examine its functional role in primary human microglia. Using siRNA, we achieved substantial PU.1 protein knock‐down in vitro . By assessing a range of characteristic microglial proteins we found decreased viability of adult human microglia with reduced PU.1 protein expression. This observation was confirmed with PU.1 antisense DNA oligonucleotides. An important function of microglia is to clear debris by phagocytosis. We assessed the impact of loss of PU.1 on microglial phagocytosis and show that PU.1 siRNA reduces the ability of adult human microglia to phagocytose amyloid‐beta 1‐42 peptide. These results show that PU.1 controls human microglial viability and function and suggest PU.1 as a molecular target for manipulation of human microglial phenotype.

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PU.1 expression is dynamically and tightly controlled during haematopoiesis to direct specification of CD34+ hematopoietic stem and progenitor cells toward myeloid and B-lymphoid lineage.
“In particular, PU.1 expression is dynamically and tightly controlled during haematopoiesis to direct the specification of CD34+ hematopoietic stem and progenitor cells toward the myeloid and B-lymphoid lineage by progressively partitioning into CD14+ monocytes/macrophages, CD15+ neutrophils, and CD19+ B cells46”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [46]
PU.1 is well known for its pivotal role in microglial development and inflammation.
“which is well known for its pivotal role in microglial development and inflammation (Fig. 7, D to F) (15, 40).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [40]
PU.1 knock-down reduces Aβ42 uptake in human microglial cells.
“We have previously reported that PU.1 regulates zymosan phagocytosis (Huang et al., 2017) and others reported that PU.1 knock-down reduces Aβ42 uptake in human microglial cells (Smith et al., 2013).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Smith et al., 2013
In primary human microglia cultures, siRNA mediated reductions in PU.1 resulted in a decrease in Amyloid-β 1-42 peptide phagocytosis.
“In primary human microglia cultures siRNA mediated reductions in PU.1 resulted in a decrease in Amyloid-β 1-42 peptide phagocytosis41, in a similar manner to observations in BV-2 cells7,32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [41]
Reduced Spi1 seems to impact cell cycle, given the involvement of PU.1 in survival signalling.
“Overall, this reinforces previous reports that reduced Spi1 seems to impact cell cycle which was not unexpected given the involvement of PU.1 in survival signalling11,41.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [41]

In human microglia cultures, siRNA-mediated reduction of PU.1 resulted in lower cell number, disintegration and rounding of some cells, but at final timepoint viability appeared unaffected.
“In human microglia cultures an siRNA mediated reduction of PU.1 resulted in a lower cell number, disintegration and rounding of some cells but at the final timepoint viability appeared unaffected. This suggests some microglia could survive with reduced PU.141.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [41]
Silencing of PU.1 by siRNA in mixed human glial culture led to reduced viability of microglia and decreased phagocytosis of amyloid-beta.
“silencing of PU.1 by siRNA in mixed human glial culture led to the reduced viability of microglia and decreased phagocytosis of amyloid-beta (A β 42) (Smith, Gibbons et al., 2013).”
From Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals (2023) · cites this paper as Smith, Gibbons et al., 2013
Silencing of PU.1 by siRNA in mixed human glial culture led to reduced viability of microglia and decreased phagocytosis of amyloid-beta (Aβ42).
“silencing of PU.1 by siRNA in mixed human glial culture led to the reduced viability of microglia and decreased phagocytosis of amyloid-beta (Aβ42) (Smith et al., 2013).”
From Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals (2025) · cites this paper as Smith et al., 2013
Spi1-knockdown decreases microglial phagocytic activity in vitro, which may lead to an increase in the levels of toxic protein aggregates and dead cell debris.
“On the contrary, Spi1-knockdown also decreases microglial phagocytic activity in vitro, which may lead to an increase in the levels of toxic protein aggregates and dead cell debris1,7.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [7]
Experimental data indicate that excessive PU.1 suppression can impair essential microglial functions.
“Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [32]
PU.1 is required for microglial identity and viability, and excessive reduction may impair essential functions.
“Because PU.1 is required for microglial identity and viability, excessive reduction may impair essential functions.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [32]
Lowering PU.1 may reduce risk-associated or inflammatory programs, but too much suppression could compromise microglial survival, plaque engagement, phagocytosis, or other protective functions.
“This creates a central tension for Alzheimer’s therapeutics: lowering PU.1 may reduce risk-associated or inflammatory programs, but too much suppression could compromise microglial survival, plaque engagement, phagocytosis, or other protective functions.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [32]
Earlier work in human microglia showed that PU.1 is critical for microglial viability and expression of characteristic microglial proteins, indicating that PU.1 cannot be viewed only as a disease-promoting factor.
“Earlier work in human microglia showed that PU.1 is critical for microglial viability and expression of characteristic microglial proteins, indicating that PU.1 cannot be viewed only as a disease-promoting factor [32].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [32]
Previous studies investigating the therapeutic potential of PU.1 for Alzheimer's disease have relied primarily on in vitro experiments using cell culture systems.
“Previous studies investigating the therapeutic potential of PU.1 for Alzheimer's disease have relied primarily on in vitro experiments using cell culture systems [22, 37, 38].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [38]
PU.1 positively regulates phagocytosis, a potentially beneficial process critical for Aβ clearance in Alzheimer's disease pathology.
“On the other hand, PU.1 positively regulates phagocytosis, a potentially beneficial process critical for Aβ clearance in Alzheimer's disease pathology [37, 38].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [38]
In early-stage Alzheimer's disease, increasing PU.1 activity may enhance microglial amyloid clearance.
“in early‐stage Alzheimer's disease, increasing PU.1 activity may enhance microglial amyloid clearance”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [38]
In R6/2 microglia, mutant HTT primes the cells by raising Pu.1, a myeloid transcription factor that promotes phagocytosis.
“Mutant HTT expression in R6/2 microglia effectively 'primes' the cell by increasing expression of the myeloid transcription factor Pu.1”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Smith et al., 2013
Silencing PU.1 by siRNA reduced the number of microglia and their ramification and phagocytosis of amyloid-beta peptide 1-42 in mixed glial culture.
“However, silencing of PU.1 by siRNA reduced the number of microglia and their ramification and phagocytosis of amyloid-beta peptide 1-42 (AB42) in mixed glial culture in their study [29].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [29]
PU.1 expression levels are similar in isolated human glial cells from biopsy and postmortem adult human brain tissues.
“PU.1 expression levels are similar in isolated human glial cells from biopsy and postmortem adult human brain tissues [29].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [29]
PU.1 is necessary for microglial differentiation and maintenance and can induce macrophages from fibroblasts.
“which is necessary for microglial differentiation and maintenance 21,22 and can induce macrophages from fibroblasts 23.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [22]

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Adult Human Microglia: Phenotypic Diversity and Functional Complexity
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Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammalsPreprint
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PU.1 expression in microglia
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Authors: Smith, A. M., Gibbons, H. M., Oldfield, R. L., Bergin, P. M., Mee, E. W., Faull, R. L. M., & Dragunow, M.
Affiliations: University of Auckland (NZ)
Lab Plus Auckland New Zealand
Corresponding author: Dragunow, Mike
ORCID: Smith, Amy M.
Bergin, Peter M.
Faull, Richard L. M.
Dragunow, Mike
Venue: Glia
Publisher: Wiley
Published: 2013-03-09
Volume: 61
Issue: 6
Pages: 929-942
ISSN: 0894-1491 (ISSN-L)
1098-1136
DOI: 10.1002/glia.22486
OpenAlex: W2101108887
Cited by: 141
References: 58
Citations by year: 2026: 12 · 2025: 23 · 2024: 8 · 2023: 12 · 2022: 21 · 2021: 14 · 2020: 13 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 3
FWCI: 2.83
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Glia (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords: PU.1, microglia, transcription factors, phagocytosis, amyloid-beta clearance, microglial phenotype, siRNA knockdown, antisense oligonucleotides, human brain
MeSH terms: Proto-Oncogene Protein Spi-1, Brain, Cell Survival, Cells, Cultured, Gene Expression Regulation, Humans, Phagocytosis, Proto-Oncogene Proteins, Trans-Activators, Microglia, RNA, Small Interfering

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The transcription factor PU.1 is critical for viability and function of human brain microglia

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