Browsing by Author "Shin, Nara"

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    Astrocytic Expression of CTMP Following an Excitotoxic Lesion in the Mouse Hippocampus
    (Korean Society of Brain & Neural Science, 2017) Shin, Nara; Yi, Min-Hee; Kim, Sena; Baek, Hyunjung; Triantafillu, Ursula L.; Park, Jongsun; Kim, Dong Woon; Chungnam National University; University of Texas Medical Branch Galveston; University of Alabama Tuscaloosa
    Akt (also known as protein kinase B, PKB) has been seen to play a role in astrocyte activation of neuroprotection; however, the underlying mechanism on deregulation of Akt signaling in brain injuries is not fully understood. We investigated the role of carboxy-terminal modulator protein (CTMP), an endogenous Akt inhibitor, in brain injury following kainic acid (KA)-induced neurodegeneration of mouse hippocampus. In control mice, there was a weak signal for CTMP in the hippocampus, but CTMP was markedly increased in the astrocytes 3 days after KA treatment. To further investigate the effectiveness of Akt signaling, the phosphorylation of CTMP was examined. KA treatment induced an increased p-CTMP expression in the astrocytes of hippocampus at 1 day. LPS/ IFN-gamma-treatment on primary astrocytes promoted the p-CTMP was followed by phosphorylation of Akt and finally upregulation of CTMP and p-CREB. Time-dependent expression of p-CTMP, p-Akt, p-CREB, and CTMP indicate that LPS/ IFN-gamma-induced phosphorylation of CTMP can activate Akt/CREB signaling, whereas lately emerging enhancement of CTMP can inhibit it. These results suggest that elevation of CTMP in the astrocytes may suppress Akt activity and ultimately negatively affect the outcome of astrocyte activation (astroglisiois). Early time point enhancers of phosphorylation of CTMP and/or late time inhibitors specifically targeting CTMP may be beneficial in astrocyte activation for neuroprotection within treatment in neuroinflammatory conditions.
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    CD200R/Foxp3-mediated signalling regulates microglial activation
    (Nature Portfolio, 2016) Yi, Min-Hee; Zhang, Enji; Kim, Jwa-Jin; Baek, Hyunjung; Shin, Nara; Kim, Sena; Kim, Sang Ryong; Kim, Hang-Rae; Lee, Sung Joong; Park, Jin Bong; Kim, Yonghyun; Kwon, O-Yu; Lee, Young Ho; Oh, Sang-Ha; Kim, Dong Woon; Chungnam National University; University of Texas Medical Branch Galveston; Yanbian University; Chungnam National University Hospital; Kyungpook National University; Seoul National University (SNU); University of Alabama Tuscaloosa
    The heterogeneity of microglial functions have either beneficial or detrimental roles in specific physiological or pathological environments. However, the details of what transcriptional mechanisms induce microglia to take beneficial phenotypes remain unknown. Here, we report that Foxp3 is essential for beneficial outcome of the microglial response and depends upon signalling by the immunoglobulin CD200 through its receptor (CD200R). Foxp3 expression was up-regulated in microglia activated by excitotoxicity-induced hippocampal neuroinflammation. Suppression of CD200R prevented anti-inflammatory phenotype of microglia, but over-expression of Foxp3 enhanced it. Phosphorylation of STAT6, a downstream effector of CD200R, modulated transcription of Foxp3. Finally, CD200R/Foxp3-mediated signalling enhanced hippocampal neuronal viability and conferred a degree of neuroprotection, presumably by counteracting inducible nitric oxide synthase. We conclude that enhancement of Foxp3 through CD200R could be neuroprotective by targeting the microglia.
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    Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model
    (Nature Portfolio, 2015) Zhang, Enji; Yi, Min-Hee; Shin, Nara; Baek, Hyunjung; Kim, Sena; Kim, Eunjee; Kwon, Kisang; Lee, Sunyeul; Kim, Hyun-Woo; Bae, Yong Chul; Kim, Yonghyun; Kwon, O. -Yu; Lee, Won Hyung; Kim, Dong Woon; Chungnam National University; Chungnam National University Hospital; Kyungpook National University; Yanbian University; University of Alabama Tuscaloosa
    Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, but its role in neuropathic pain remains unclear. In this study, we examined the ER stress and the unfolded protein response (UPR) activation in a L5 spinal nerve ligation (SNL)-induced rat neuropathic pain model. SNL-induced neuropathic pain was assessed behaviorally using the CatWalk system, and histologically with microglial activation in the dorsal spinal horn. L5 SNL induced BIP upregulation in the neuron of superficial laminae of dorsal spinal horn. It also increased the level of ATF6 and intracellular localization into the nuclei in the neurons. Moreover, spliced XBP1 was also markedly elevated in the ipsilateral spinal dorsal horn. The PERK-elF2 pathway was activated in astrocytes of the spinal dorsal horn in the SNL model. In addition, electron microscopy revealed the presence of swollen cisternae in the dorsal spinal cord after SNL. Additionally, inhibition of the ATF6 pathway by intrathecal treatment with ATF6 siRNA reduced pain behaviors and BIP expression in the dorsal horn. The results suggest that ER stress might be involved in the induction and maintenance of neuropathic pain. Furthermore, a disturbance in UPR signaling may render the spinal neurons vulnerable to peripheral nerve injury or neuropathic pain stimuli.
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    Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons
    (Biomed Central, 2017) Baek, Hyunjung; Shin, Hyo Jung; Kim, Jwa-Jin; Shin, Nara; Kim, Sena; Yi, Min-Hee; Zhang, Enji; Hong, Jinpyo; Kang, Joon Won; Kim, Yonghyun; Kim, Cuk-Seong; Kim, Dong Woon; Chungnam National University; Chungnam National University Hospital; University of Texas Medical Branch Galveston; Yanbian University; University of Alabama Tuscaloosa
    Background: The primary cilium is an organelle that can act as a master regulator of cellular signaling. Despite the presence of primary cilia in hippocampal neurons, their function is not fully understood. Recent studies have demonstrated that the primary cilium influences interleukin (IL)-1 beta-induced NF-kappa B signaling, ultimately mediating the inflammatory response. We, therefore, investigated ciliary function and NF-kappa B signaling in lipopolysaccharide (LPS)-induced neuroinflammation in conjunction with ciliary length analysis. Methods: Since TLR4/NF-kappa B signaling is a well-known inflammatory pathway, we measured ciliary length and inflammatory mediators in wild type (WT) and TLR4(-/-) mice injected with LPS. Next, to exclude the effects of microglial TLR4, we examined the ciliary length, ciliary components, inflammatory cytokine, and mediators in HT22 hippocampal neuronal cells. Results: Primary ciliary length decreased in hippocampal pyramidal neurons after intracerebroventricular injection of LPS in WT mice, whereas it increased in TLR4(-/-) mice. LPS treatment decreased primary ciliary length, activated NF-kappa B signaling, and increased Cox2 and iNOS levels in HT22 hippocampal neurons. In contrast, silencing Kif3a, a key protein component of cilia, increased ARL13B ciliary protein levels and suppressed NF-kappa B signaling and expression of inflammatory mediators. Conclusions: These data suggest that LPS-induced NF-kappa B signaling and inflammatory mediator expression are modulated by cilia and that the blockade of primary cilium formation by Kif3a siRNA regulates TLR4-induced NF-kappa B signaling. We propose that primary cilia are critical for regulating NF-kappa B signaling events in neuroinflammation and in the innate immune response.
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    TLR4-mediated autophagic impairment contributes to neuropathic pain in chronic constriction injury mice
    (Biomed Central, 2018) Piao, Yibo; Gwon, Do Hyeong; Kang, Dong-Wook; Hwang, Tae Woong; Shin, Nara; Kwon, Hyeok Hee; Shin, Hyo Jung; Yin, Yuhua; Kim, Jwa-Jin; Hong, Jinpyo; Kim, Hyun-Woo; Kim, Yonghyun; Kim, Sang Ryong; Oh, Sang-Ha; Kim, Dong Woon; Chungnam National University; Chungnam National University Hospital; University of Alabama Tuscaloosa; Kyungpook National University
    Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial Toll-like receptor 4 (TLR4) and autophagy are implicated in neurodegenerative diseases, but their relationship and role in neuropathic pain remain unclear. In this study, we examined TLR4 and its association with autophagic activity using a chronic constriction injury (CCI)-induced neuropathic pain model in wild-type (WT) and TLR4-knockout (KO) mice. The mice were assigned into four groups: WT-Contralateral (Contra), WT-Ipsilateral (Ipsi), TLR4 KO-Contra, and TLR4 KO-Ipsi. Behavioral and mechanical allodynia tests and biochemical analysis of spinal cord tissue were conducted following CCI to the sciatic nerve. Compared with the Contra group, mechanical allodynia in both the WT-and TLR4 KO-Ipsi groups was significantly increased, and a marked decrease of allodynia was observed in the TLR4 KO-Ipsi group. Although glial cells were upregulated in the WT-Ipsi group, no significant change was observed in the TLR4 KO groups. Moreover, protein expression and immunoreactive cell regulation of autophagy (Beclin 1, p62) were significantly increased in the neurons, but not microglia, of WT-Ipsi group compared with the WT-Contra group. The level of PINK1, a marker for mitophagy was increased in the neurons of WT, but not in TLR4 KO mice. Together, these results show that TLR4-mediated p62 autophagic impairment plays an important role in the occurrence and development of neuropathic pain. And what is more, microglial TLR4-mediated microglial activation might be indirectly coupled to neuronal autophage.