2. Academic Validation
  3. Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization

Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization

  • PLoS Biol. 2023 Jul 24;21(7):e3002199. doi: 10.1371/journal.pbio.3002199.
Pinyi Liu 1,  Yan Chen 1,  Zhi Zhang 1,  Zengqiang Yuan 2 3,  Jian-Guang Sun 2 3,  Shengnan Xia 1,  Xiang Cao 1,  Jian Chen 1,  Cun-Jin Zhang 1,  Yanting Chen 1,  Hui Zhan 1,  Yuexinzi Jin 1,  Xinyu Bao 1,  Yue Gu 1,  Meijuan Zhang 1,  Yun Xu 1 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
  • 2 The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 3 Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China.
  • 4 Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China.
  • 5 Nanjing Neurology Clinic Medical Center, Nanjing, China.
  • 6 Institute of Brain Sciences, Nanjing University, Nanjing, China.
  • 7 Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
PMID: 37486903 DOI: 10.1371/journal.pbio.3002199
Abstract

Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.

Figures
Products
Inhibitors & Agonists
Other Products