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mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia
Open accessAbstract
Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in poststroke neuroinflammation are largely unexplored. In this study, we injected rapamycin, a mTOR inhibitor, by the intracerebroventricular route 6 h after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of γδ T cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of proinflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization toward the M1 type. In addition, we also found that rapamycin significantly enhanced anti-inflammation activity of regulatory T cells (Tregs), which decreased production of proinflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the anti-inflammation activity of Tregs to restrain poststroke neuroinflammation.
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“which were previously involved in restricting amyloidosis56, microglial response to pathogens57, and pro-inflammatory microglia58”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [58]
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Metadata
- Authors
- Xie, L., Sun, F., Wang, J., Mao, X., Xie, L., Yang, S.-H., Su, D.-M., Simpkins, J. W., Greenberg, D. A., & Jin, K.
- Affiliations
- Buck Institute for Research on Aging (US)
- University of North Texas Health Science Center (US)
- West Virginia University (US)
- Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center , Fort Worth, TX 76107
- Corresponding author
- Xie, Luokun
- Sun, Fen
- Wang, Jixian
- ORCID
- Sun, Fen
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-06
- Volume
- 192
- Issue
- 12
- Pages
- 6009-6019
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4128178
- OpenAlex
- W1618035875
- Cited by
- 175
- References
- 76
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 19 · 2022: 11 · 2021: 26 · 2020: 12 · 2019: 19 · 2018: 15 · 2017: 18 · 2016: 21 · 2015: 12 · 2014: 2
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Research Repository @ WVU (West Virginia University) (submittedVersion)
- Funders
- University of North Texas
- National Institute on Aging (R01AG021980, AG21980, P01AG027956)
- National Institute of General Medical Sciences (U54GM104942)
- National Institute of Neurological Disorders and Stroke (NS57186, NS054651, NS054687, R01NS054687, R01NS057186, R01NS054651)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- mTOR signaling, rapamycin, focal ischemic stroke, regulatory T cells, macrophage polarization, microglia, γδ T cells, granulocytes, inflammatory cytokines, chemokines, secondary brain injury, motor impairment, intracerebroventricular administration
- MeSH terms
- Animals, Brain Ischemia, Immunosuppressive Agents, Inflammation, Macrophages, Male, Signal Transduction, Receptors, Antigen, T-Cell, gamma-delta, Rats, Sprague-Dawley, Microglia, Sirolimus, Stroke, T-Lymphocytes, Regulatory, Rats, TOR Serine-Threonine Kinases
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