Neutralization of tumor necrosis factor-related apoptosis-inducing ligand reduces spinal cord injury damage in mice.

Abstract

Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly on the extent of damage in which proapoptotic cytokines have a crucial function. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the function of the proapoptotic cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Immunostaining for TRAIL and its receptor DR5 was found in the white and gray matter of the perilesional area, as also confirmed by western blotting experiments. Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-alpha, IL-1beta, and MPO), and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax, and Bcl-2 expression). As glucocorticoid-induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with upregulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR(-/-)) in comparison with wild-type mice suggesting that TRAIL- and GITRL-activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.

• Authors: Giuseppina Cantarella, Giulia Di Benedetto, Mimmo Scollo, Irene Paterniti, Salvatore Cuzzocrea, Paolo Bosco, Giuseppe Nocentini, Carlo Riccardi, Renato Bernardini
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 35 Issue 6 Pg. 1302-14 (May 2010) ISSN: 1740-634X [Electronic] England
• PMID: 20107429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Apoptosis Regulatory Proteins
• Inflammation Mediators
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Tnfsf10 protein, mouse
• Tnfsf18 protein, mouse
• Tumor Necrosis Factors

Topics

• Animals
• Antibodies, Neutralizing (pharmacology, therapeutic use)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Disease Models, Animal
• Inflammation (drug therapy, metabolism, physiopathology)
• Inflammation Mediators (metabolism)
• Male
• Mice
• Mice, Knockout
• Receptors, TNF-Related Apoptosis-Inducing Ligand (drug effects, metabolism)
• Spinal Cord Injuries (drug therapy, metabolism, physiopathology)
• TNF-Related Apoptosis-Inducing Ligand (antagonists & inhibitors, immunology, metabolism)
• Tumor Necrosis Factors (genetics)