MIF promotes neurodegeneration and cell death via its nuclease activity following traumatic brain injury

Zhi Ruan, Qing Lu, Jennifer E. Wang, Mi Zhou, Shuiqiao Liu, Hongxia Zhang, Akshay Durvasula, Yijie Wang, Yanan Wang, Weibo Luo, Yingfei Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Traumatic brain injury (TBI), often induced by sports, car accidents, falls, or other daily occurrences, is a primary non-genetically related risk factor for the development of subsequent neurodegeneration and neuronal cell death. However, the molecular mechanisms underlying neurodegeneration, cell death, and neurobehavioral dysfunction following TBI remain unclear. Here, we found that poly(ADP-ribose) polymerase-1 (PARP-1) was hyperactivated following TBI and its inhibition reduced TBI-induced brain injury. Macrophage migration inhibitory factor (MIF), a newly identified nuclease involved in PARP-1-dependent cell death, was translocated from the cytosol to the nucleus in cortical neurons following TBI and promoted neuronal cell death in vivo. Genetic deletion of MIF protected neurons from TBI-induced dendritic spine loss, morphological complexity degeneration, and subsequent neuronal cell death in mice. Moreover, MIF knockout reduced the brain injury volume and improved long-term animal behavioral rehabilitation. These neuroprotective effects in MIF knockout mice were reversed by the expression of wild-type MIF but not nuclease-deficient MIF mutant. In contrast, genetic deletion of MIF did not alter TBI-induced neuroinflammation. These findings reveal that MIF mediates TBI-induced neurodegeneration, neuronal cell death and neurobehavioral dysfunction through its nuclease activity, but not its pro-inflammatory role. Targeting MIF’s nuclease activity may offer a novel strategy to protect neurons from TBI.

Original languageEnglish (US)
Article number39
JournalCellular and Molecular Life Sciences
Volume79
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • Cell death
  • MIF
  • Neurodegeneration
  • Traumatic brain injury

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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