Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity
Open accessAbstract
Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e., when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer's and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer's Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments.
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In response to LPS injection, male C57BL/6 microglia elicit an aged phenotype characterized by heightened upregulation of immune gene expression relative to female-derived microglia.
“This work showed that in response to LPS injection, male C57BL/6 microglia elicit an aged phenotype characterized by heightened upregulation of immune gene expression relative to female derived microglia.”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [103]
The Methods (Animals; LPS treatments and tissue collection) identify C57BL/6 mice and an LPS injection. The Results (Sex difference in microglial developmental index response to LPS challenge) report that male, but not female, microglia shifted toward a more mature developmental profile after LPS; the Results (Gene expression changes in microglia following an immune challenge are related to development) link that profile to immune-related genes. The paper does not call it an aged phenotype, and it says the overall magnitude of the male and female transcriptional responses was similar, rather than establishing heightened immune-gene upregulation in males overall. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSex has effects on microglial morphology, gene expression, and function.
“There is some precedent for sex having effects on microglial morphology, gene expression, and function. 33 , 34 , 35”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [33]
Brains from individuals with Alzheimer's disease exhibit "older" microglial signatures than age-matched controls.
“Brains from individuals with Alzheimer’s disease were also found to exhibit “older” microglial signatures than age-matched controls.”
Healthy human male brains exhibit "older" microglial signatures than age-matched female brains.
“healthy human male brains were found to exhibit “older” microglial signatures than age-matched female brains.”
A comprehensive developmental study by Hanamsagar et al. (2017) observed that transcriptionally, male and female microglia are quite similar until early adulthood (P60).
“A comprehensive developmental study by Hanamsagar et al. (2017) observed that transcriptionally, male and female microglia are quite similar until early adulthood (P60).”
From Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system (2023) · cites this paper as Hanamsagar et al. (2017)
Transcriptome analysis of aged human microglia reveals specific genes influenced by aging.
“Transcriptome analysis of aged human microglia reveal specific genes influenced by aging [52-54].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [54]
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Do Microglial Sex Differences Contribute to Sex Differences in Neurodegenerative Diseases?
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Isolation of Microglia from Mouse or Human Tissue
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Adolescence is a sensitive period for prefrontal microglia to act on cognitive development
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Sex differences in tissue-specific immunity and immunology
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Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity
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Microbiome Gut-Brain-Axis: Impact on Brain Development and Mental Health
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- Authors
- Hanamsagar, R., Alter, M. D., Block, C. S., Sullivan, H., Bolton, J. L., & Bilbo, S. D.
- Affiliations
- Harvard University (US)
- University of Pennsylvania (US)
- Department of Psychology and Neuroscience Duke University Durham North Carolina 27708
- Duke University (US)
- Corresponding author
- Hanamsagar, Richa
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2017-06-15
- Volume
- 65
- Issue
- 9
- Pages
- 1504-1520
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC5540146
- OpenAlex
- W2977622316
- Cited by
- 384
- References
- 37
- Citations by year
- 2026: 24 · 2025: 33 · 2024: 60 · 2023: 44 · 2022: 51 · 2021: 44 · 2020: 35 · 2019: 37 · 2018: 39 · 2017: 17
- FWCI
- 17.25
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institute of Mental Health (R01MH101183)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- microglial development, sex differences, microglial maturation, transcriptional programs, lipopolysaccharide, neuroinflammation, Alzheimer's disease, autism spectrum disorder, human brain transcriptome, brain development, microglia
- MeSH terms
- Animals, Cells, Cultured, Escherichia coli, Female, Hippocampus, Humans, Lipopolysaccharides, Male, Mice, Inbred C57BL, Sex Characteristics, Neuroimmunomodulation, Microglia, Gene Expression Regulation, Developmental, Gene Expression Profiling, Estrous Cycle, Mice
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