Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain

Xu, Ni; Wu, Mingzheng; Deng, Xiaheng; Ma, Pingchuan; Li, Ze-Hua; Liang, Lin; Xia, Mengfan; Cui, Dong; He, Duan-duan; Zong, Ying; Xie, Zhong; Song, Xue-Jun

doi:10.1523/jneurosci.0800-16.2016

Cited by 27 publications

(36 citation statements)

References 33 publications

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“…To evaluate the effects of Peli1 on established neuropathic pain behavior, 5 μg Peli1 siRNA or 5 μg negative siRNA was intrathecally administrated daily for 3 consecutive days during postoperative days 5-7. The dosages of siRNA were selected based on previous reports [28]. Thermal hyperalgesia and mechanical allodynia were measured before and 3, 5, 7, 9 days after CCI.…”

Section: Experimental Designmentioning

confidence: 99%

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Wang

Chen

Liu

et al. 2020

J Neuroinflammation

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Background: Spinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely determined. Here, we investigated the role of Pellino1 (Peli1) and its interplay with spinal microglial activation in neuropathic pain. Methods: In this study, we examined the effects of Peli1 on pain hypersensitivity and spinal microglial activation after chronic constriction injury (CCI) of the sciatic nerve in mice. The molecular mechanisms involved in Peli1mediated hyperalgesia were determined by western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We utilized immunoprecipitation to examine the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) following CCI. In addition, we explored the effect of Peli1 on BV2 microglial cells in response to lipopolysaccharide (LPS) challenge. Results: We found that CCI induced a significant increase in the levels of Peli1, which was present in the great majority of microglia in the spinal dorsal horn. Our results showed that spinal Peli1 contributed to the induction and maintenance of CCI-induced neuropathic pain. The biochemical data revealed that CCI-induced Peli1 in the spinal cord significantly increased mitogen-activated protein kinase (MAPK) phosphorylation, activated nuclear factor kappa B (NF-κB), and enhanced the production of proinflammatory cytokines, accompanied by spinal microglial activation. Peli1 additionally was able to promote K63-linked ubiquitination of TRAF6 in the ipsilateral spinal cord following CCI. Furthermore, we demonstrated that Peli1 in microglial cells significantly enhanced inflammatory reactions after LPS treatment. Conclusion: These results suggest that the upregulation of spinal Peli1 is essential for the pathogenesis of neuropathic pain via Peli1-dependent mobilization of spinal cord microglia, activation of MAPK/NF-κB signaling, and production of proinflammatory cytokines. Modulation of Peli1 may serve as a potential approach for the treatment of neuropathic pain.

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Section: Experimental Designmentioning

confidence: 99%

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Wang

Chen

Liu

et al. 2020

J Neuroinflammation

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“…Interestingly, knockdown of FRMD6 led to a nuclear accumulation of YAP through a reduction of a series of phosphorylation events, including p-MST1/2, p-LAST1 and finally p-YAP, in the rat spinal dorsal horn. Moreover, an intrathecal FRMD6 siRNA application induced a long-lasting mechanical allodynia, indicating an analgesic role of FRMD6 in spinal cord 35 . The present results suggest that the lower levels of cytoplasmic FRMD6 in injured DRG neurons may attenuate its inhibitory action on the Hippo signaling pathway, that is nuclear YAP will be upregulated and could then promote neuropathic pain.…”

Section: Discussionmentioning

confidence: 93%

“…Conversely, decreased levels of FRMD6 lead to translocation of YAP from cytoplasm to nucleus, inducing transcriptional activation, which can result in opposite effects, including increased cell proliferation 7,14 . It has been shown that a chronic sciatic nerve construction induces nuclear accumulation of YAP/TAZ in the spinal dorsal horn 35 . Moreover, spinal inhibition or knockdown of YAP/TAZ significantly suppresses mechanical allodynia 35 .…”

Section: Discussionmentioning

confidence: 99%

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Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Lyu

Mulder

et al. 2020

Sci Rep

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FRMD6, a member of the group of FERM-domain proteins, is involved both in communication between cells, interactions with extracellular matrix, cellular apoptotic and regenerative mechanisms. FRMD6 was first discovered in the rodent sciatic nerve, and in the present immunohistochemical study we investigated the distribution of FRMD6 in the dorsal root ganglia (DRGs), sciatic nerve and spinal cord following sciatic nerve injury. FRMD6-immunoreactivity was found in the cytoplasm, nucleus or both, and in a majority of DRG neurons. FRMD6-immunoreactivity co-existed with several wellknown neuronal markers, including calcitonin gene-related peptide, isolectin B4 and neurofilament 200 in mouse DRGs. After peripheral nerve injury, the FRMD6 mRNA levels and the overall percentage of FRMD6-positive neuron profiles (NPs) were decreased in ipsilateral lumbar DRGs, the latter mainly affecting small size neurons with cytoplasmic localization. Conversely, the proportion of NPs with nuclear FRMD6-immunoreactivity was significantly increased. In the sciatic nerve, FRMD6immunoreactivity was observed in non-neuronal cells and in axons, and accumulated proximally to a ligation of the nerve. In the spinal cord FRMD6-immunoreactivity was detected in neurons in both dorsal and ventral horns, and was upregulated in ipsilateral dorsal horn after peripheral nerve axotomy. Our results demonstrate that FRMD6 is strictly regulated by peripheral nerve injury at the spinal level. FRMD (protein 4.1, ezrin, radixin and moesin) 6, also known as Willin, is a member of the 4.1 superfamily and was first identified in the sciatic nerve of rats by northern blot analysis 1. Recently, the FRMD6 transcripts were detected in mouse lumbar dorsal root ganglia (DRGs) and spinal cord by RNAseq (see Supplementary Table 4) 2. Human FRMD6 has been shown to be a homolog of Ex in Drosophila, which is a putative tumor suppressor 3,4. FRMD6/Ex, as an upstream regulator, is a component of multiple upstream molecular complexes in the Salvador/ Warts/Hippo (Hippo) signaling pathway network that, mostly via MST1/2 (mammalian STE20-like protein kinase) and LATS1/2 (large tumour suppressor homolog), regulates the activity of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), two downstream homologous transcriptional co-activators 5-8. This pathway, originally identified in drosophila 9,10 and more recently shown to be well conserved in mammalians 11 , regulates cellular proliferation, differentiation, apoptosis and tissue homoeostasis 5,6. In human, analysing tissues from healthy and diseased donors by immunohistochemistry, FRMD6-immunoreactivity was observed in cytoplasm, plasma membrane or nucleus of various normal tissues (e.g., intestine) and carcinoma, and sometimes with a mixed intracellular distribution 12. However, the functional associations between these subcellular localizations and physiopathologic processes are still not elucidated. Moreover, FRMD6 transcripts were detected predominantly in fibroblasts within the perine...

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“…Visceral pain is caused by injury or inflammation of internal organs and can be constant if the pain originates from a solid organ, or intermittent in the form of cramps, or colic as a result of obstructions in hollow organs. Neuropathic pain is caused by injury, inflammation, or dysfunction of the central or peripheral nervous system [14]. Patients may have mixed pain consisting of somatic, visceral, and neuropathic pain all at the same time or each separately at different times.…”

Section: Types Of Pain In Childrenmentioning

confidence: 99%

Analgesia in the palliative care of children

et al. 2020

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Due to the increasing incidence of terminal illnesses in children, there is great urgency within pediatric medicine to give these patients the best palliative care possible. The main focus of palliative care is to alleviate suffering resulting from the psychophysical condition of the child, which is mostly due to physical pain. The first phase of managing pain in palliative care is quantifying and qualifying pain levels, although this is sometimes difficult to do with pediatric patients. In addition to implementing strategies that alleviate or remove pain for patients, it is also crucial to give patients and their families a feeling of full control over pain. In practice, non-pharmacological and pharmacological methods of analgesia are present. Pharmacological methods include non-opioid and opioid analgesics, followed by co-analgesics as well as methods of regional anesthesia. In order to give these patients the best care possible, it is necessary that the approach be individual, multimodal, multidisciplinary, and considerate of every detail.

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Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain

Cited by 27 publications

References 33 publications

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Analgesia in the palliative care of children

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