Bromodomain and extraterminal domain-containing protein inhibition attenuates acute inflammation after spinal cord injury

Michelle D. Rudman, James S. Choi, Ha Eun Lee, Sze Kiat Tan, Nagi Ayad, Jae Lee

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Inflammation is a major contributor to the secondary damage that occurs after spinal cord injury (SCI). The inflammatory response is coordinated by many different signaling modalities including the epigenetic modification of promoters and enhancers. Bromodomain and extraterminal domain-containing proteins (BETs; Brd2, Brd3, Brd4, BrdT) are epigenetic readers that bind acetylated histones to promote transcription of pro-inflammatory genes. BET inhibition is anti-inflammatory in animal models of cancer, rheumatoid arthritis, and coronary artery disease. However, the role of BETs in neuroinflammation remains largely unexplored. In this study, we investigated the role of BETs in promoting inflammation in neural cells and the ability of the BET inhibitor JQ1 to decrease inflammation acutely after SCI. Expression of BET mRNA was assessed via qPCR in purified primary mouse macrophages, astrocytes, neurons, oligodendrocytes, and microglia, as well as in naïve, sham-injured, and contusion-injured mouse spinal cord. Brd2, Brd3, and Brd4 mRNA were expressed in all purified primary neural cells and in the uninjured and injured mouse spinal cord. BET inhibition significantly attenuated proinflammatory signaling in all activated cell populations in vitro. To investigate the effects of BET modulation after SCI, the BET inhibitor JQ1 was injected intraperitoneally (30 mg/kg, bidaily) 3 h after spinal cord contusion in adult female C57BL/6 mice. By 3 days post-injury, BET inhibition significantly decreased pro-inflammatory cytokine expression and leukocyte recruitment to the injury site. However, this decrease did not lead to locomotor improvements or smaller lesion size. Taken together, our data implicate BETs as regulators of multiple key pro-inflammatory cytokines, and suggest that BETs can be pharmacologically inhibited to reduce inflammation acutely after SCI.

Original languageEnglish (US)
Pages (from-to)181-192
Number of pages12
JournalExperimental Neurology
Volume309
DOIs
StatePublished - Nov 1 2018

Keywords

  • (+)-JQ1
  • Astrocytes
  • Epigenetic reader
  • Epigenetics
  • Macrophages
  • Microglia
  • Neurons
  • Neuroprotection
  • Neutrophils
  • Oligodendrocytes

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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