Chemokine CCL2-CCR2 signaling induces neuronal cell death via STAT3 activation and IL-1β production after status epilepticus

Dai Shi Tian, Jiyun Peng, Madhuvika Murugan, Li Jie Feng, Jun Li Liu, Ukpong B. Eyo, Li Jun Zhou, Rochelle Mogilevsky, Wei Wang, Long Jun Wu

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2-CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1GFP/+:CCR2RFP/+ double-transgenic mice, we demonstrated that CCL2-CCR2 signaling has a role in resident microglial activation and blood-derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3(signal transducerand activator of transcription 3)phosphorylation and IL-1β production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066reduced seizure-induced IL-1β production and subsequent neuronal death. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2-CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1β production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy.

Original languageEnglish (US)
Pages (from-to)7878-7892
Number of pages15
JournalJournal of Neuroscience
Volume37
Issue number33
DOIs
StatePublished - Aug 16 2017

Keywords

  • CCL2
  • Epilepsy
  • MCP-1
  • Microglia
  • Monocytes
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)

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