MTOR Signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia

Luokun Xie, Fen Sun, Jixian Wang, Xiao Ou Mao, Lin Xie, Shaohua Yang, Dong Ming Su, James W. Simpkins, David A. Greenberg, Kunlin Jin

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Abstract

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 antiinflammation 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 antiinflammation activity of Tregs to restrain poststroke neuroinflammation.

Original languageEnglish
Pages (from-to)6009-6019
Number of pages11
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - 15 Jun 2014

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Microglia
Regulatory T-Lymphocytes
Sirolimus
Ischemia
Macrophages
Wounds and Injuries
Chemokines
Stroke
Cytokines
Brain
Adaptive Immunity
Granulocytes
Innate Immunity
T-Lymphocytes

Cite this

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title = "MTOR Signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia",
abstract = "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 antiinflammation 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 antiinflammation activity of Tregs to restrain poststroke neuroinflammation.",
author = "Luokun Xie and Fen Sun and Jixian Wang and Mao, {Xiao Ou} and Lin Xie and Shaohua Yang and Su, {Dong Ming} and Simpkins, {James W.} and Greenberg, {David A.} and Kunlin Jin",
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MTOR Signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. / Xie, Luokun; Sun, Fen; Wang, Jixian; Mao, Xiao Ou; Xie, Lin; Yang, Shaohua; Su, Dong Ming; Simpkins, James W.; Greenberg, David A.; Jin, Kunlin.

In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 6009-6019.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - MTOR Signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia

AU - Xie, Luokun

AU - Sun, Fen

AU - Wang, Jixian

AU - Mao, Xiao Ou

AU - Xie, Lin

AU - Yang, Shaohua

AU - Su, Dong Ming

AU - Simpkins, James W.

AU - Greenberg, David A.

AU - Jin, Kunlin

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