The Orphan Nuclear Receptor Nr4a1 Mediates Perinatal Neuroinflammation in a Murine Model of Preterm Labor
Journal Article - Open Access
MADIGAN ARMY MEDICAL CENTER JOINT BASE LEWIS MCCHORD WA JOINT BASE LEWIS MCCHORD United States
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Prematurity is associated with perinatal neuroinflammation and injury. Screening for genetic modulators in an LPS murine model of preterm birth revealed the upregulation of Nr4a1, an orphan nuclear transcription factor that is normally absent or limited in embryonic brains. Concurrently, Nr4a7 was downregulated with magnesium sulfate MgSO4 and betamethasone BMTZ treatments administered to LPS exposed dams. To understand the role of Nr4a1 in perinatal brain injury, we compared the preterm neuroinflammatory response in Nr4a1 knockout KO versus wildtype wt mice. Key inflammatory factors ll1b, ll6 and Tnf, and lba1 microglia were significantly lower in Nr4a1 KO versus wt brains exposed to LPS in utero. Treatment with MgSO4BMTZ mitigated the neuroinflammatory process in wt but not Nr4a1 KO brains. These results correspond with a reduction in cerebral hemorrhage in wt but not mutant embryos from dams given MgSO4BMTZ. Further analysis with Nr4a1-GFP-Cre x tdTomato loxP reporter mice revealed that the upregulation of Nr4a1 with perinatal neuroinflammation occurs in the cerebral vasculature. Altogether, this study implicates Nr4a7 in the developing vasculature as a potent mediator of neuroinflammatory brain injury that occurs with preterm birth. It is also possible that MgSO4BMTZ mitigates this process by direct or indirect inhibition of Nr4a7.
- Anatomy and Physiology
- Medicine and Medical Research