Fas/FasL-mediated apoptosis and inflammation are key features of acute human spinal cord injury: implications for translational, clinical application.
The Fas/FasL system plays an important role in apoptosis, the inflammatory response and gliosis in a variety of neurologic disorders. A better understanding of these mechanisms could lead to effective therapeutic strategies following spinal cord injury (SCI). We explored these mechanisms by examining molecular changes in postmortem human spinal cord tissue from cases with acute and chronic SCI. Complementary studies were conducted using the in vivo Fejota™ clip compression model of SCI in Fas-deficient B6.MRL-Fas-lpr (lpr) and wild-type (Wt) mice to test Fas-mediated apoptosis, inflammation, gliosis and axonal degeneration by immunohistochemistry, Western blotting, gelatin zymography and ELISA with Mouse 32-plex cytokine/chemokine panel bead immunoassay. We report novel evidence that shows that Fas-mediated apoptosis of neurons and oligodendrocytes occurred in the injury epicenter in all cases of acute and subacute SCI and not in chronic SCI or in control cases. We also found significantly reduced apoptosis, expression of GFAP, NF-κB, p-IKappaB and iba1, increased number of CD4 positive T cells and MMP2 expression and reduced neurological dysfunction in lpr mice when compared with Wt mice after SCI. We found dramatically reduced inflammation and cytokines and chemokine expression in B6.MRL-Fas-lpr mice compared to Wt mice after SCI. In conclusion, we report multiple lines of evidence that Fas/FasL activation plays a pivotal role in mediating apoptosis, the inflammatory response and neurodegeneration after SCI, providing a compelling rationale for therapeutically targeting Fas in human SCI.
Division of Genetics and Development, Toronto Western Research Institute and Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada.
Wen Ru
WR
Yu
Michael G
MG
Fehlings
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015704:CD4 Antigens / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000502:physiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D008875:Middle Aged; D023421:Models, Animal; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000473:pathology*; D012189:Retrospective Studies; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019014:fas Receptor / Q000502:physiology*
D015704:CD4 Antigens; D016207:Cytokines; D053222:Fas Ligand Protein; D005904:Glial Fibrillary Acidic Protein; D019014:fas Receptor