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

J Immunol. 2014 Jun 15;192(12):6009-19. doi: 10.4049/jimmunol.1303492. Epub 2014 May 14.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy
  • Brain Ischemia / immunology*
  • Brain Ischemia / pathology
  • Immunosuppressive Agents / pharmacology
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Microglia / immunology*
  • Microglia / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Sirolimus / pharmacology
  • Stroke / immunology*
  • Stroke / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / immunology*

Substances

  • Immunosuppressive Agents
  • Receptors, Antigen, T-Cell, gamma-delta
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Sirolimus