Gamma interferon alters junctional integrity via rho kinase, resulting in blood-brain barrier leakage in experimental viral encephalitis.
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In an experimental viral encephalitis mouse model in which mice are infected with reovirus, we show that IFN-γ induces blood-brain barrier leakage. We show that IFN-γ promotes Rho kinase activity, resulting in actin cytoskeletal contractions in the brain endothelium that lead to vascular junctional disorganization and cell-cell separations. These studies now provide insight into a previously unknown mechanism for how blood-brain barrier breakdown occurs in viral encephalitis and implicates IFN-γ-Rho kinase activity as major contributor to this phenomenon. By identifying this mechanism of blood-brain barrier breakdown, we now provide potential therapeutic targets in treating patients with viral causes of encephalitis with the hope of limiting damage to the central nervous system.
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Cytokine administration into the cisterna magna of mice is sufficient to drive arachnoid barrier and blood-cerebral spinal fluid barrier functional breakdown, and activated T cells in the leptomeninges produce cytokines known to perturb tight junction integrity of brain endothelial cells, including IFNγ which is known to drive BBB breakdown in viral encephalitis.
“cytokine administration into the cisterna magna of mice is sufficient to drive arachnoid barrier and blood-cerebral spinal fluid barrier functional breakdown”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Bonney et al., 2019
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Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
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- Authors
- Bonney, S., Seitz, S., Ryan, C. A., Jones, K. L., Clarke, P., Tyler, K. L., & Siegenthaler, J. A.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Tyler, Kenneth L.
- Siegenthaler, Julie A.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-08-27
- Volume
- 10
- Issue
- 4
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6686045
- OpenAlex
- W2965238134
- Cited by
- 79
- References
- 63
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 15 · 2021: 11 · 2020: 11 · 2019: 1
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Department of Veterans Affairs (5101BX000963)
- HHS | NIH | National Cancer Institute (P30CA046934)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (5R33AI101064)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (F31NS100565, R01NS098273, R01NS076512)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR057212)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- interferon-gamma, Rho kinase, blood-brain barrier disruption, viral encephalitis, reovirus, endothelial junctions, therapeutic target
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Disease Models, Animal, Female, Humans, Interferon-gamma, Male, Reoviridae Infections, Mammalian orthoreovirus 3, Encephalitis, Viral, Endothelial Cells, Mice, rho-Associated Kinases
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