Genetic analysis of the role of tumor necrosis factor receptors in functional outcome after traumatic brain injury in mice.
We previously reported that tumor necrosis factor-alpha (TNF-alpha) and Fas receptor induce acute cellular injury, tissue damage, and motor and cognitive deficits after controlled cortical impact (CCI) in mice (Bermpohl et al. 2007 ); however, the TNF receptors (TNFR) involved are unknown. Using a CCI model and novel mutant mice deficient in TNFR1/Fas, TNFR2/Fas, or TNFR1/TNFR2/Fas, we tested the hypothesis that the combination of TNFR2/Fas is protective, whereas TNFR1/Fas is detrimental after CCI. Uninjured knockout (KO) mice showed no differences in baseline physiological variables or motor or cognitive function. Following CCI, mice deficient in TNFR2/Fas had worse post-injury motor and Morris water maze (MWM) performance than wild-type (WT) mice (p < 0.05 group effect for wire grip score and MWM performance by repeated measures ANOVA). No differences in motor or cognitive outcome were observed in TNFR1/Fas KO, or in TNFR2 or TNFR1 single KO mice, versus WT mice. Additionally, no differences in propidium iodide (PI)-positive cells (at 6 h) or lesion size (at 14 days) were observed between WT and TNFR1/Fas or TNFR2/Fas KO mice. Somewhat surprisingly, mice deficient in TNFR1/TNFR2/Fas also had PI-positive cells, lesion size, and motor and MWM deficits similar to those of WT mice. These data suggest a protective role for TNFR2/Fas in the pathogenesis of TBI. Further studies are needed to determine whether direct or indirect effects of TNFR1 deletion in TNFR2/Fas KO mice mediate improved functional outcome in TNFR1/TNFR2/Fas KO mice after CCI.
Yang
Jinsheng
J
Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
You
Zerong
Z
Kim
Hyung-Hwan
HH
Hwang
Seo-Kyoung
SK
Khuman
Jugta
J
Guo
Shuzhen
S
Lo
Eng H
EH
Whalen
Michael J
MJ
D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000503:physiopathology; D002452:Cell Count; D005838:Genotype; D016489:Head Injuries, Closed / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D020127:Recovery of Function / Q000235:genetics*; D013037:Spatial Behavior; D016896:Treatment Outcome
D018124:Receptors, Tumor Necrosis Factor