Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4/NF-κB pathway

Lin Liu; Yingtong Xu; Hongmei Dai; Shan Tan; Xiao Mao; Zhiheng Chen

doi:10.1186/s13578-020-00387-2

Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4/NF-κB pathway

Cell Biosci. 2020 Mar 17:10:42. doi: 10.1186/s13578-020-00387-2. eCollection 2020.

Authors

Lin Liu¹, Yingtong Xu¹, Hongmei Dai¹, Shan Tan¹, Xiao Mao², Zhiheng Chen¹

Affiliations

¹ 1Department of Pediatrics, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Yuelu District, ChangshaHunan, 410013 China.
² Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, ChangshaHunan, 410008 China.

Abstract

Background: Microglia-mediated neuroinflammation is associated with epilepsy. Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for mitigating epileptogenesis. We previously found that dynorphins protected against epilepsy via activation of kappa opioid receptor (KOR). Here, this study aims to investigate the role and the mechanism of dynorphin in regulating microglial polarization.

Methods: A pilocarpine-induced rat model of epilepsy was established and lipopolysaccharide (LPS)-activated BV-2 microglial cells were used as an inflammatory model to explore the mechanism of dynorphin regulating microglial polarization.

Results: Overexpression of the dynorphin precursor protein prodynorphin (PDYN) alleviated the pilocarpine-induced neuronal apoptosis, promoted microglial polarization to the M2 phenotype, and inhibited pilocarpine-induced Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway in the hippocampi of epileptic rats. Dynorphin activation of KOR promoted microglial M2 polarization via inhibiting TLR4/NF-κB pathway in LPS-stimulated BV-2 microglial cells. Moreover, dynorphin/KOR regulated microglial M2 polarization inhibited apoptosis of the primary mouse hippocampal neurons.

Conclusion: In conclusion, dynorphin activation of KOR promotes microglia polarization toward M2 phenotype via inhibiting TLR4/NF-κB pathway.

Keywords: Dynorphin; M1; M2 polarization; Microglia; NF-κb; Prodynorphin; TLR4.