The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.
The transcription factor PU.1 is critical for viability and function of human brain microglia
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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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 the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2013-03-09
- Volume
- 61
- Issue
- 6
- Pages
- 929-942
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- 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
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › 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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