Attenuated neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered neuroinflammation following traumatic brain injury

• Published in: Brain research 2011-09, Vol.1414, p.94-105
• Main Authors: Ziebell, Jenna M, Bye, Nicole, Semple, Bridgette D, Kossmann, Thomas, Morganti-Kossmann, Maria Cristina
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Analysis of Variance; Animals; Biological and medical sciences; brain; brain damage; Brain Injuries - complications; Caspase; Caspase 3 - metabolism; Cell death; Cell Death - genetics; chemotaxis; Cytokine; Cytokines - metabolism; Disease Models, Animal; Fas; Fas Ligand Protein - immunology; fas Receptor - genetics; Glial Fibrillary Acidic Protein - metabolism; Humans; Immunoglobulin G - therapeutic use; In Situ Nick-End Labeling - methods; inflammation; Injuries of the nervous system and the skull. Diseases due to physical agents; interleukin-12; interleukin-6; intravenous injection; macrophages; Macrophages - drug effects; Medical sciences; Mice; Mice, Inbred MRL lpr; Microglia - drug effects; Mutation - genetics; Nervous System Diseases - drug therapy; Nervous System Diseases - genetics; Nervous System Diseases - pathology; neuroglia; Neuroinflammation; Neurology; neuroprotective effect; neutralization; neutralizing antibodies; Organic mental disorders. Neuropsychology; Phosphopyruvate Hydratase - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Time Factors; Traumas. Diseases due to physical agents; Traumatic brain injury; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.07.056

Abstract Progressive neurodegeneration following traumatic brain injury (TBI) involves the Fas and TNF-receptor1 protein systems which have been implicated in mediating delayed cell death. In this study, we used two approaches to assess whether inhibition of these pathways reduced secondary brain damage and neurological deficits after TBI. Firstly, we investigated whether the expression of non-functional Fas in lpr mice subjected to TBI altered tissue damage and neurological outcome. Compared to wild-type, lpr mice showed improved neurological deficit (p = 0.0009), decreased lesion volume (p = 0.017), number of TUNEL+ cells (p = 0.011) and caspase-3+ cells (p = 0.007). Changes in cellular inflammation and cytokine production were also compared between mouse strains. Accumulation of macrophages/microglia occurred earlier in lpr mice, likely due to enhanced production of the chemotactic mediators IL-12(p40) and MCP-1 (p < 0.05). Cortical production of IL-1α and IL-6 increased after injury to a similar extent regardless of strain (p < 0.05), while TNF and G-CSF were significantly higher in lpr animals (p < 0.05). Secondly, we assessed whether therapeutic inhibition of FasL and TNF via intravenous injection of neutralizing antibodies in wild-type mice post-TBI could reproduce the beneficial effects observed in lpr animals. No differences were found with this approach in animals treated with anti-FasL and anti-TNF antibodies alone or the combination of both. Altogether, reduced neurological deficits and lesion volume in lpr mice was associated with altered cellular and humoral inflammation, possibly contributing to neuroprotection, whereas neutralization of FasL and TNF had no effect. In future studies, the lpr mouse strain may be utilized as a model to further characterize molecular and cellular mechanisms protecting against secondary brain damage after TBI.