mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia.
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.
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107;
Luokun
L
Xie
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107;
Fen
F
Sun
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;
Jixian
J
Wang
Buck Institute for Research on Aging, Novato, CA 94945; and.
XiaoOu
X
Mao
Buck Institute for Research on Aging, Novato, CA 94945; and.
Lin
L
Xie
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107;
Shao-Hua
SH
Yang
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107;
Dong-Ming
DM
Su
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.
James W
JW
Simpkins
Buck Institute for Research on Aging, Novato, CA 94945; and.
David A
DA
Greenberg
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.
Kunlin
K
Jin
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D020521:Stroke / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
D007166:Immunosuppressive Agents; D016692:Receptors, Antigen, T-Cell, gamma-delta; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus