Targeted mutation of Fas ligand gene attenuates brain inflammation in experimental stroke

Brain Behav Immun. 2012 Jan;26(1):61-71. doi: 10.1016/j.bbi.2011.07.235. Epub 2011 Jul 23.


Inflammation is an important contributing mechanism in ischemic brain injury. The current study elucidates a previously unexplored role of Fas ligand (FasL) in post-stroke inflammatory responses that is independent of its well-known effect in triggering apoptosis. Focal cerebral ischemia was induced for 2 h by right middle cerebral artery occlusion (MCAO) in FasL mutant (gld) and wild-type mice. FasL mutation profoundly reduced brain damage and improved neurological performance from 6 to 72 h after ischemic stroke. The production of inflammatory cytokines in the brain was attenuated in gld mice after ischemia in the absence of dramatic change in inflammatory cell apoptosis. FasL mutation attenuated the recruitment of peripheral inflammatory cells (neutrophil) and inhibited the activation of residential glial cells (microglia and astrocyte). FasL mutation reduced CD8(+) T cells and turned the Th1/Th2 balance towards Th2 in the brain and peripheral blood after cerebral ischemia. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of lipopolysaccharide (LPS) were also attenuated in gld mice. Moreover, the soluble FasL (sFasL) and phospho-SAPK/JNK were decreased in gld mice, suggesting that the inflammatory role of FasL in experimental stroke might relate to sFasL and the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our data suggest a novel role of FasL in the damaging inflammatory responses associated with cerebral ischemia. Neutralization of FasL may be a novel therapeutic strategy to suppress post-stroke inflammation and improve the long-term outcomes of stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Brain / pathology*
  • Brain Edema / pathology
  • Brain Ischemia / genetics
  • Brain Ischemia / pathology
  • Cell Count
  • Cerebral Infarction / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Fas Ligand Protein / genetics*
  • Flow Cytometry
  • Gene Targeting
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / pathology
  • Inflammation / genetics*
  • Inflammation / pathology*
  • Injections, Intraventricular
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / physiology
  • Proto-Oncogene Proteins c-jun / genetics
  • Real-Time Polymerase Chain Reaction
  • Stroke / genetics*
  • Stroke / pathology*


  • Fas Ligand Protein
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-jun