Toll-like receptor-4 knockout mice are more resistant to optic nerve crush damage than wild-type mice

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

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Optic Nerve Crush: Axonal Responses in Wild-Type and bcl-2 Transgenic Mice

Journal of Neuroscience ◽

10.1523/jneurosci.19-19-08367.1999 ◽

1999 ◽

Vol 19 (19) ◽

pp. 8367-8376 ◽

Cited By ~ 85

Author(s):

Sabrina Chierzi ◽

Enrica Strettoi ◽

Maria Cristina Cenni ◽

Lamberto Maffei

Keyword(s):

Optic Nerve ◽

Transgenic Mice ◽

Optic Nerve Crush ◽

Wild Type ◽

Nerve Crush

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Retinal Ganglion Cell Loss is Delayed Following Optic Nerve Crush in NLRP3 Knockout Mice

Scientific Reports ◽

10.1038/srep20998 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 24

Author(s):

Zhen Puyang ◽

Liang Feng ◽

Hui Chen ◽

Peiji Liang ◽

John B. Troy ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Knockout Mice ◽

Cell Loss ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush

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Effect of Brimonidine on Retinal Ganglion Cell Survival in an Optic Nerve Crush Model

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(09)79071-4 ◽

2009 ◽

Vol 2009 ◽

pp. 74-75

Author(s):

J. Leavitt

Keyword(s):

Optic Nerve ◽

Ganglion Cell ◽

Cell Survival ◽

Retinal Ganglion Cell ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Retinal Ganglion Cell Survival

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Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

Anesthesiology ◽

10.1097/aln.0b013e3182608cc0 ◽

2012 ◽

Vol 117 (2) ◽

pp. 329-338 ◽

Cited By ~ 34

Author(s):

Willem-Jan M. Schellekens ◽

Hieronymus W. H. van Hees ◽

Michiel Vaneker ◽

Marianne Linkels ◽

P. N. Richard Dekhuijzen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Caspase 3 ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Diaphragm Atrophy ◽

Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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