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Irf8 exacerbates hypertensive intracerebral hemorrhage by mediating a pro-inflammatory phenotype of microglia through
Jingkun Wu1, Liang Hou1, Qinghua Zhu1
1Department 2 of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan 056000, Hebei, PR China.
Abstract:
Interferon regulatory factor 8 (Irf8) is a transcription factor expressed only in the microglia in the brain and directs the expression of many genes that serve microglial functions. This report investigates the role of Irf8 in microglia during the progression of hypertensive intracerebral hemorrhage (ICH). L-NAME and angiotensin II initiated the ICH mouse model after stereotactic injection of knockdown and overexpression vectors. Inflammatory responses were induced in the mouse microglia cell line BV-2 using lipopolysaccharide (LPS), and lentiviral infection was conducted to manipulate gene expression. Irf8 was significantly overexpressed in the brain tissues of ICH mice and LPS-induced BV-2 cells. Downregulation of Irf8 hampered microglial M1 polarization and the inflammatory response and partially alleviated limb dysfunction caused by neurological impairment resulting from ICH. Irf8 interacted with the signal transducer and activator of transcription 1 (Stat1), thus mediating the transcriptional activation of Stat1 on tripartite motif-containing protein 5 (Trim5) in microglia. Overexpression of Trim5 reversed the inhibitory effect of sh-Irf8 on the inflammatory response in microglia and exacerbated cerebral hemorrhage in ICH mice. Thus, it was suggested that Irf8 overexpression activated the Stat1/Trim5 axis and mediated a microglial proinflammatory phenotype, thereby exacerbating hypertensive ICH.
Insights
Interferon regulatory factor 8 (Irf8) drives microglial inflammation in hypertensive intracerebral hemorrhage (ICH). Downregulating Irf8 reduces inflammation and neurological deficits, suggesting Irf8 as a therapeutic target for ICH.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are key immune cells in the brain.
- Interferon regulatory factor 8 (Irf8) is a transcription factor critical for microglial function.
- Hypertensive intracerebral hemorrhage (ICH) involves significant neuroinflammation.
Purpose of the Study:
- To investigate the role of Irf8 in microglial activation during hypertensive ICH.
- To elucidate the molecular mechanisms by which Irf8 influences neuroinflammation in ICH.
Main Methods:
- Established a mouse model of ICH using L-NAME and angiotensin II.
- Utilized stereotactic injections of knockdown and overexpression vectors for Irf8.
- Induced inflammatory responses in BV-2 microglial cells with LPS and manipulated gene expression via lentiviral infection.
Main Results:
- Irf8 was significantly overexpressed in ICH mouse brains and LPS-stimulated BV-2 cells.
- Irf8 downregulation reduced M1 microglial polarization, inflammation, and neurological deficits in ICH mice.
- Irf8 was found to interact with Stat1, mediating the transcriptional activation of Trim5, and this axis exacerbated ICH.
Conclusions:
- Irf8 overexpression promotes a pro-inflammatory microglial phenotype in ICH.
- The Irf8-Stat1-Trim5 axis plays a crucial role in exacerbating hypertensive ICH.
- Targeting Irf8 may offer a therapeutic strategy for mitigating ICH progression.
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