Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization.
Pinyi LiuYan ChenZhi ZhangZengqiang YuanJian-Guang SunShengnan XiaXiang CaoJian ChenCun-Jin ZhangYanting ChenHui ZhanYuexinzi JinXinyu BaoYue GuMeijuan ZhangYun XuPublished in: PLoS biology (2023)
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.
Keyphrases
- binding protein
- inflammatory response
- transcription factor
- neuropathic pain
- poor prognosis
- rheumatoid arthritis
- lipopolysaccharide induced
- mouse model
- atrial fibrillation
- lps induced
- oxidative stress
- traumatic brain injury
- anti inflammatory
- spinal cord
- spinal cord injury
- long non coding rna
- metabolic syndrome
- dna binding
- cerebral ischemia
- weight loss
- insulin resistance
- subarachnoid hemorrhage