IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype
Open accessAbstract
Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation.
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The microglial signature in human Alzheimer's disease resembles the IRF8-driven reactive microglia seen after peripheral nerve injury.
“Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [27]
This human Alzheimer's disease microglial signature is remarkably similar to the IRF8-driven reactive phenotype that mouse microglia adopt after peripheral nerve injury.
“This signature was remarkably similar to the IRF8-driven reactive phenotype that mouse microglia adopt in peripheral nerve injury (PNI)27.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [27]
This signature evokes the reactive microglia phenotype described in a mouse peripheral nerve injury model that is driven at least in part by IRF8 and MafB.
“This signature evokes the reactive microglia phenotype described in a mouse model of PNI that is driven, at least in part, by IRF827 and MafB42.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [27]
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Self-citation
- Authors
- Masuda, T., Tsuda, M., Yoshinaga, R., Tozaki-Saitoh, H., Ozato, K., Tamura, T., & Inoue, K.
- Affiliations
- Kyushu University (JP)
- National Institutes of Health (US)
- Yokohama City University (JP)
- Corresponding author
- Tsuda, Makoto
- Inoue, Kazuhide
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 1
- Issue
- 4
- Pages
- 334-340
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4158926
- OpenAlex
- W2156821568
- Cited by
- 338
- References
- 34
- Citations by year
- 2026: 17 · 2025: 35 · 2024: 30 · 2023: 33 · 2022: 27 · 2021: 32 · 2020: 22 · 2019: 24 · 2018: 20 · 2017: 26 · 2016: 22 · 2015: 14 · 2014: 22 · 2013: 11 · 2012: 3
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (23659492, 24390246, 23890148, 24118002)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD001310)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- IRF8, microglial activation, reactive microglia, transcription factors, peripheral nerve injury, neuropathic pain, spinal cord, microglial gene expression
- MeSH terms
- Interferon Regulatory Factor-8, Animals, Gene Expression Regulation, Mice, Inbred C57BL, Pain, Phenotype, Spinal Cord, Transcription, Genetic, Microglia, Cell Proliferation, Interferon Regulatory Factors, Mice, Peripheral Nerve Injuries
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