Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner
Open accessAbstract
BACKGROUND: Chronic microglia-mediated inflammation and oxidative stress are well-characterized underlying factors in neurodegenerative disease, whereby reactive inflammatory microglia enhance ROS production and impact neuronal integrity. Recently, it has been shown that during chronic inflammation, neuronal integrity is compromised through targeted disruption of the axon initial segment (AIS), the axonal domain critical for action potential initiation. AIS disruption was associated with contact by reactive inflammatory microglia which wrap around the AIS, increasing association with disease progression. While it is clear that chronic microglial inflammation and enhanced ROS production impact neuronal integrity, little is known about how acute microglial inflammation influences AIS stability. Here, we demonstrate that acute neuroinflammation induces AIS structural plasticity in a ROS-mediated and calpain-dependent manner. METHODS: mice were given a single injection of lipopolysaccharide (LPS; 5 mg/kg) or vehicle (0.9% saline, 10 mL/kg) and analyzed at 6 h-2 weeks post-injection. Anti-inflammatory Didox (250 mg/kg) or vehicle (0.9% saline, 10 mL/kg) was administered beginning 24 h post-LPS injection and continued for 5 days; animals were analyzed 1 week post-injection. Microglial inflammation was assessed using immunohistochemistry (IHC) and RT-qPCR, and AIS integrity was quantitatively analyzed using ankyrinG immunolabeling. Data were statistically compared by one-way or two-way ANOVA where mean differences were significant as assessed using Tukey's post hoc analysis. RESULTS: LPS-induced neuroinflammation, characterized by enhanced microglial inflammation and increased expression of ROS-producing enzymes, altered AIS protein clustering. Importantly, inflammation-induced AIS changes were reversed following resolution of microglial inflammation. Modulation of the inflammatory response using anti-inflammatory Didox, even after significant AIS disruption occurred, increased the rate of AIS recovery. qPCR and IHC analysis revealed that expression of microglial NOX2, a ROS-producing enzyme, was significantly increased correlating with AIS disruption. Furthermore, ablation of NOX2 prevented inflammation-induced AIS plasticity, suggesting that ROS drive AIS structural plasticity. CONCLUSIONS: In the presence of acute microglial inflammation, the AIS undergoes an adaptive change that is capable of spontaneous recovery. Moreover, recovery can be therapeutically accelerated. Together, these findings underscore the dynamic capabilities of this domain in the presence of a pathological insult and provide evidence that the AIS is a viable therapeutic target.
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Ptgs2 (COX2) and Cybb (Nox-2) are considered proinflammatory mediators.
“Based on publicly available data in this model (Krasemann et al., 2017), we focused on the expression of the two highest induced genes upon repeated systemic LPS injections, Ptgs2 and Cybb (also known as Cox2 and Nox-2 respectively), where both genes are considered as proinflammatory mediators (Alhadidi and Shah, 2018; Benusa et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Benusa et al., 2017
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- Authors
- Benusa, S. D., George, N. M., Sword, B. A., DeVries, G. H., & Dupree, J. L.
- Affiliations
- Virginia Commonwealth University (US)
- Hunter Holmes McGuire VA Medical Center (US)
- Corresponding author
- Dupree, J. L.
- Venue
- Journal of Neuroinflammation
- Published
- 2017-06-08
- Volume
- 14
- Issue
- 1
- Pages
- 116-116
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC5465457
- OpenAlex
- W2622610015
- Cited by
- 31
- References
- 86
- Citations by year
- 2026: 4 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 9 · 2018: 3 · 2017: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs (5IO1BX002565, 101BX001759)
- National Institute of Neurological Disorders and Stroke (5P30NS047463)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- axon initial segment, acute neuroinflammation, microglial inflammation, reactive microglia, NADPH oxidase 2, reactive oxygen species, calpain, lipopolysaccharide, didox, ankyrin-G, action potential generation, oxidative stress, neurodegenerative diseases
- MeSH terms
- Axon Initial Segment, NADPH Oxidase 2, Animals, Cerebral Cortex, Female, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Neuronal Plasticity, Reactive Oxygen Species, Microglia, Mice, Knockout, Mice
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