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Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord.
J Neuroinflammation. 2020 Mar 14; 17(1):83.JN

Abstract

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 Peli1-mediated 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.

Authors+Show Affiliations

School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China.School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China.School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China. Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, China.School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China.Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, China.School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China. caojl0310@aliyun.com. Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. caojl0310@aliyun.com.School of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221002, China. lucoct@163.com. Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. lucoct@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32171293

Citation

Wang, Lijuan, et al. "Pellino1 Regulates Neuropathic Pain as Well as Microglial Activation Through the Regulation of MAPK/NF-κB Signaling in the Spinal Cord." Journal of Neuroinflammation, vol. 17, no. 1, 2020, p. 83.
Wang L, Yin C, Liu T, et al. Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord. J Neuroinflammation. 2020;17(1):83.
Wang, L., Yin, C., Liu, T., Abdul, M., Zhou, Y., Cao, J. L., & Lu, C. (2020). Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord. Journal of Neuroinflammation, 17(1), 83. https://doi.org/10.1186/s12974-020-01754-z
Wang L, et al. Pellino1 Regulates Neuropathic Pain as Well as Microglial Activation Through the Regulation of MAPK/NF-κB Signaling in the Spinal Cord. J Neuroinflammation. 2020 Mar 14;17(1):83. PubMed PMID: 32171293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord. AU - Wang,Lijuan, AU - Yin,Cui, AU - Liu,Tianya, AU - Abdul,Mannan, AU - Zhou,Yan, AU - Cao,Jun-Li, AU - Lu,Chen, Y1 - 2020/03/14/ PY - 2019/09/06/received PY - 2020/02/21/accepted PY - 2020/3/16/entrez PY - 2020/3/17/pubmed PY - 2020/3/17/medline KW - MAPK signaling KW - Microglial activation KW - NF-κB KW - Neuroinflammation KW - Neuropathic pain KW - Pellino1 SP - 83 EP - 83 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 17 IS - 1 N2 - 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 Peli1-mediated 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/32171293/Pellino1_regulates_neuropathic_pain_as_well_as_microglial_activation_through_the_regulation_of_MAPK/NF_κB_signaling_in_the_spinal_cord_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01754-z DB - PRIME DP - Unbound Medicine ER -