KLF4 Knockdown Attenuates TBI-Induced Neuronal Damage through p53 and JAK-STAT3 Signaling.
OBJECTIVE
Traumatic brain injury (TBI) is induced by complex primary and secondary mechanisms that give rise to cell death, inflammation, and neurological dysfunction. Understanding the mechanisms that drive neurological damage as well as those that promote repair can guide the development of therapeutic drugs for TBI. Kruppel-like factor 4 (KLF4) has been reported to negatively regulate axon regeneration of injured retinal ganglion cells (RGCs) through inhibition of JAK-STAT3 signaling. However, the role of KLF4 in TBI remains unreported. Reactive oxygen species (ROS)-induced neuronal death is a pathophysiological hallmark of TBI.


METHODS
In this study, we used H2O2-treated RGCs in vitro and the optic nerve crush model in vivo to simulate neuronal damage in TBI. The function of KLF4 in RGC survival and axon regeneration in these models was investigated. In addition, the effects of KLF4 knockdown on neuronal damage after a brain impact that mimics moderate TBI were studied.


RESULTS
The results show that H2O2induces p53-dependent apoptosis of RGCs in vitro through upregulation of KLF4. Additionally, KLF4 knockdown in vivo significantly enhances CNTF-induced axon regeneration of RGCs after optic nerve crush, and more importantly, prevents neuronal damage after a moderate brain impact in rats. Our Western blot analysis and immunoprecipitation assay results indicate that these effects of KLF4 knockdown are mediated by the p53 and JAK-STAT3 pathways.


CONCLUSIONS
These findings provide evidence that KLF4 plays an important role in the pathophysiology of TBI. Blocking KLF4 may be a potential therapeutic strategy for the treatment of TBI, either alone or in combination with agents that target complementary mechanisms.
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Da-Ming
DM
Cui
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Tao
T
Zeng
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Jie
J
Ren
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Ke
K
Wang
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Yi
Y
Jin
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Lin
L
Zhou
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Liang
L
Gao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000070642:Brain Injuries, Traumatic / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D020221:Optic Nerve Injuries / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D019938:Cyclin D1; D006861:Hydrogen Peroxide; D053612:Janus Kinases
Kruppel-like factor 4; Nrf2; P53; STAT3; Traumatic brain injury
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