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
  • 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.

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