ArticleProceedings of the National Academy of Sciences of the United States of America2020
Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 2 of them syntheses that pooled it.
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Who cites it
109 citing papers in PubMed, 2 syntheses or guidelines pooled it, 187 citations in OpenAlex.
- Integrating cell-type-specific gene expression and genome-wide associations identifies risk genes for schizophrenia.Molecular psychiatry · 2026Pooled it
- Lentivirus- or AAV-mediated gene therapy interventions in ischemic stroke: A systematic review of preclinicalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2022Pooled it
- The role of IRF5 as an immune regulator.Biochemical Society transactions · 2026Review
- CCDC50 Alleviates Cerebral Ischemia-Reperfusion Injury via Enhancing Autophagy to Inhibit STING/IRF3-Mediated Microglial Polarization.Molecular neurobiology · 2026Article
- Interferon regulatory factor 4-releasing 3D-printed scaffolds enhance spinal cord repair by modulating macrophage polarization.Neural regeneration research · 2026Article
- Identifying a Csmd3Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Heme Oxygenase-1 Contributes to Dampening Proinflammatory Activation in the Human Microglial Cell Line HMC3 and Controls the Transcription Factor IRF5.Biomolecules · 2026Article
- Macrophage immunometabolism in stroke: a view from single-cell and nano technologies.Journal of translational medicine · 2026Review
- SREBP2 promotes macrophage alternative activation and allergic airway inflammation independent of cholesterol biosynthesis.Cell death & disease · 2026Article
- Toosendanin Alleviates Cerebral Ischemia/Reperfusion Injury via Inhibiting Neural Ferroptosis Through Lipid Metabolic Reprogramming in MCAO Mice.CNS neuroscience & therapeutics · 2026Article
- A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction.Journal of neuroinflammation · 2026Article
- Peripheral inhibition of IL-6 signaling with tocilizumab improves stroke outcomes in aged mice but requires sex-specific dosing.bioRxiv : the preprint server for biology · 2026Article
- P2X7 Receptor Inhibition Mitigates Microglial Activation, Neuroinflammation, and Secondary Thalamic Damage After Ischemic Stroke.Molecular neurobiology · 2026Article
- A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction.Research square · 2026Article
- Peripheral CD200R signaling: A critical regulator of post-stroke inflammation in aged mice.Brain research bulletin · 2026Article
- Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Glycolysis-related gene signatures in spinal cord injury pathophysiology identification through integrative gene expression analysis.Frontiers in genetics · 2026Article
- Interferon regulatory factors: the next prospective targets for tissue ischemia-reperfusion injury?Frontiers in immunology · 2026Review
- Lysine Demethylase 5B Alleviates Neuroinflammation in Ischemic Stroke by Repressing Steap4.Cell biochemistry and biophysics · 2025Article
49 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Microglial activation plays a central role in poststroke inflammation and causes secondary neuronal damage; however, it also contributes in debris clearance and chronic recovery. Microglial pro- and antiinflammatory responses (or so-called M1-M2 phenotypes) coexist and antagonize each other throughout the disease progress. As a result of this balance, poststroke immune responses alter stroke outcomes. Our previous study found microglial expression of interferon regulatory factor 5 (IRF5) and IRF4 was related to pro- and antiinflammatory responses, respectively. In the present study, we genetically modified the IRF5 and IRF4 signaling to explore their roles in stroke. Both in vitro and in vivo assays were utilized; IRF5 or IRF4 small interfering RNA (siRNA), lentivirus, and conditional knockout (CKO) techniques were employed to modulate IRF5 or IRF4 expression in microglia. We used a transient middle cerebral artery occlusion model to induce stroke and examined both acute and chronic stroke outcomes. Poststroke inflammation was evaluated with flow cytometry, RT-PCR, MultiPlex, and immunofluorescence staining. An oscillating pattern of the IRF5-IRF4 regulatory axis function was revealed. Down-regulation of IRF5 signaling by siRNA or CKO resulted in increased IRF4 expression, enhanced M2 activation, quenched proinflammatory responses, and improved stroke outcomes, whereas down-regulation of IRF4 led to increased IRF5 expression, enhanced M1 activation, exacerbated proinflammatory responses, and worse functional recovery. Up-regulation of IRF4 or IRF5 by lentivirus induced similar results. We conclude that the IRF5-IRF4 regulatory axis is a key determinant in microglial activation. The IRF5-IRF4 regulatory axis is a potential therapeutic target for neuroinflammation and ischemic stroke.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.