PMID- 24829408 OWN - NLM STAT- MEDLINE DCOM- 20140818 LR - 20211203 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 192 IP - 12 DP - 2014 Jun 15 TI - mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. PG - 6009-19 LID - 10.4049/jimmunol.1303492 [doi] AB - 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 gammadelta 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. CI - Copyright (c) 2014 by The American Association of Immunologists, Inc. FAU - Xie, Luokun AU - Xie L AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; FAU - Sun, Fen AU - Sun F AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; FAU - Wang, Jixian AU - Wang J AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; FAU - Mao, XiaoOu AU - Mao X AD - Buck Institute for Research on Aging, Novato, CA 94945; and. FAU - Xie, Lin AU - Xie L AD - Buck Institute for Research on Aging, Novato, CA 94945; and. FAU - Yang, Shao-Hua AU - Yang SH AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; FAU - Su, Dong-Ming AU - Su DM AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; FAU - Simpkins, James W AU - Simpkins JW AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; Department of Physiology and Pharmacology, Center for Neuroscience, Health Science Center, West Virginia University, Morgantown, WV 26506. FAU - Greenberg, David A AU - Greenberg DA AD - Buck Institute for Research on Aging, Novato, CA 94945; and. FAU - Jin, Kunlin AU - Jin K AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107; kunlin.jin@unthsc.edu. LA - eng GR - P01 AG027956/AG/NIA NIH HHS/United States GR - R01 AG021980/AG/NIA NIH HHS/United States GR - AG21980/AG/NIA NIH HHS/United States GR - NS054687/NS/NINDS NIH HHS/United States GR - R01 NS054687/NS/NINDS NIH HHS/United States GR - U54 GM104942/GM/NIGMS NIH HHS/United States GR - NS57186/NS/NINDS NIH HHS/United States GR - R01 NS057186/NS/NINDS NIH HHS/United States GR - R01 NS054651/NS/NINDS NIH HHS/United States GR - NS054651/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140514 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Immunosuppressive Agents) RN - 0 (Receptors, Antigen, T-Cell, gamma-delta) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Brain Ischemia/drug therapy/*immunology/pathology MH - Immunosuppressive Agents/pharmacology MH - Inflammation/drug therapy/immunology/pathology MH - Macrophages/*immunology/pathology MH - Male MH - Microglia/*immunology/pathology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Antigen, T-Cell, gamma-delta/immunology MH - Signal Transduction/drug effects/*immunology MH - Sirolimus/pharmacology MH - Stroke/*immunology/pathology MH - T-Lymphocytes, Regulatory/*immunology/pathology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*immunology PMC - PMC4128178 MID - NIHMS587595 EDAT- 2014/05/16 06:00 MHDA- 2014/08/19 06:00 PMCR- 2015/06/15 CRDT- 2014/05/16 06:00 PHST- 2014/05/16 06:00 [entrez] PHST- 2014/05/16 06:00 [pubmed] PHST- 2014/08/19 06:00 [medline] PHST- 2015/06/15 00:00 [pmc-release] AID - jimmunol.1303492 [pii] AID - 10.4049/jimmunol.1303492 [doi] PST - ppublish SO - J Immunol. 2014 Jun 15;192(12):6009-19. doi: 10.4049/jimmunol.1303492. Epub 2014 May 14.