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Quotation: Yao Y (2023) NR4A1 destabilizes TNF mRNA in microglia and modulates stroke outcomes. PLoS Biol 21(7):
e3002226.
https://doi.org/10.1371/journal.pbio.3002226
Revealed: July 25, 2023
Copyright: © 2023 Yao Yao. That is an open entry article distributed underneath the phrases of the Inventive Commons Attribution License, which allows unrestricted use, distribution, and copy in any medium, supplied the unique writer and supply are credited.
Funding: This work was partially supported by NIH grants (RF1AG065345, R21AG073862, R21AG064422, and R01HL146574) to YY. The funders had no function in examine design, knowledge assortment and evaluation, resolution to publish, or preparation of the manuscript.
Competing pursuits: The authors have declared that no competing pursuits exist.
Microglia are brain-resident immune cells that symbolize 5% to 12% of the glial inhabitants [1]. Beneath physiological situations, microglia take a ramified morphology (small mobile physique and lengthy processes) and continually survey the mind microenvironment by extending and retracting their processes [1,2]. Upon damage or in neurological issues, microglia shortly change to an ameboid morphology (massive mobile physique and brief processes) and alter their transcriptional profiles [1,2]. Relying on the inflammatory mediators secreted, reactive microglia can take a pro-inflammatory or anti-inflammatory state. The previous features to kill pathogens, whereas the latter is concerned in particles clearance and damage restore [1,3]. Imbalance between the pro-inflammatory and anti inflammatory states causes harm and impacts damage decision [1,3]. What regulates the pro-inflammatory and anti inflammatory polarization of microglia, nonetheless, just isn’t absolutely understood.
Nuclear receptor subfamily 4 group A member 1 (NR4A1), a transcription issue and speedy early gene, is quickly induced in macrophages and microglia. Purposeful research have revealed an anti-inflammatory function for NR4A1 in macrophages in each atherosclerosis and continual irritation fashions [4–6]. Equally, NR4A1 inhibits microglial activation and pro-inflammatory gene expression in animal fashions of Parkinson’s illness and a number of sclerosis [7,8]. These findings recommend that NR4A1 restricts unrestrained irritation in microglia and macrophages. Nonetheless, the underlying molecular mechanism stays largely elusive.
On this problem of PLOS Biology, Liu and colleagues [9] report a novel posttranscriptional mechanism that mediates the regulatory impact of NR4A1 on the expression of pro-inflammatory cytokine-tumor necrosis issue (TNF) in microglia (Fig 1). Particularly, the authors discover that cytoplasmic NR4A1 straight binds to and destabilizes TNF mRNA in an N6-methyladenosine (m6A)-dependent method. Subsequent, they present that NR4A1 is up-regulated within the cytoplasm of activated microglia and localizes to processing our bodies (P-bodies) in vitro. Per the in vitro outcomes, NR4A1 ranges are elevated in microglia after ischemic stroke in each rodents and people. Utilizing NR4A1 international knockout mice, Liu and colleagues additional display that lack of NR4A1 results in elevated TNF expression and worse outcomes in a mouse mannequin of ischemic stroke. Since NR4A1 can also be expressed in non-microglial cells, together with macrophages and T cells, the authors additional generate mutant mice with NR4A1 deficiency in microglia solely utilizing the microglia-specific TMEM119-CreERT2 line. Much like the NR4A1 international knockout mice, lack of NR4A1 in microglia particularly ends in elevated TNF expression and aggravated outcomes after ischemic stroke. These findings strongly point out that microglial NR4A1 regulates TNF expression and stroke pathogenesis.
Fig 1. NR4A1 performs a neuroprotective function in stroke by regulating the expression of pro-inflammatory cytokines in microglia.
(A) Within the cytoplasm, NR4A1 diminishes the expression of TNF posttranscriptionally by binding to and destabilizing TNF mRNA. Within the nucleus, NR4A1 negatively regulates the synthesis of IL-1β and IL-6 on the transcription stage as a transcription issue. Thus, wild-type microglia produce comparatively low ranges of pro-inflammatory cytokines, resulting in reasonable stroke outcomes. (B) Lack of NR4A1 in microglia will increase the manufacturing of pro-inflammatory cytokines (TNF, IL-1β, and IL-6), resulting in aggravated stroke outcomes. This determine was created with BioRender.com.
The work by Liu and colleagues is novel and intriguing because it identifies a beforehand unidentified function of NR4A1 as an RNA-binding protein, highlights a brand new regulatory mechanism of TNF expression in microglia, and underscores a key operate of NR4A1 in microglial polarization and stroke outcomes. These findings present new molecular targets with therapeutic potential. For instance, NR4A1 could also be up-regulated to lower the manufacturing of pro-inflammatory cytokines in microglia and attenuate their pro-inflammatory polarization. This can probably ameliorate neuroinflammation and enhance neurological signs in stroke and neurodegenerative issues. Since pro-inflammatory microglia play an vital function in pathogen clearance, NR4A1 up-regulation might irritate damage in infectious ailments. As well as, the timing of NR4A1 activation may additionally have an effect on illness development and outcomes. Subsequently, it is very important examine the therapeutic results of NR4A1 manipulation in numerous neurological ailments and at a number of time factors.
Subsequent, whether or not NR4A1 makes use of an identical mechanism to manage the expression of different pro-inflammatory cytokines must be validated in vivo. Though each in vitro and in vivo research help the speculation that NR4A1 negatively regulates TNF expression in microglia, proof supporting NR4A1’s inhibitory function within the expression of different pro-inflammatory cytokines (e.g., IL-1β and IL-6) is just present in vitro. Find out how to reconcile the totally different outcomes of IL-1β and IL-6 expression in vitro and in vivo? Based mostly on the statement that up-regulated NR4A1 is especially present in microglial cytoplasm in vivo however in each cytoplasm and nucleus in vitro, the authors speculate that totally different pro-inflammatory cytokines are regulated by NR4A1 via distinct mechanisms. Particularly, cytoplasmic NR4A1 regulates TNF expression posttranscriptionally through binding to and destabilizing TNF mRNA, whereas nuclear NR4A1 regulates the expression of IL-1β and IL-6 on the transcriptional stage as a transcription issue. This speculation is additional confirmed by expressing NR4A1 completely within the cytoplasm. What confers the totally different subcellular distribution of NR4A1 in vitro and in vivo, nonetheless, stays unknown and ought to be explored sooner or later. This info will enable fine-tuning of neuroinflammation, which can probably improve the efficacy and scale back the unwanted side effects of potential therapies.
As well as, it stays unclear which area of NR4A1 binds to m6A websites and the way precisely it interacts with m6A. Figuring out the particular domains that bind to m6A-modified mRNAs and understanding the dynamics of such interplay will present insights into the molecular mechanism of microglial activation and promote the event of novel therapies for numerous neurological ailments.
Lastly, the translational potential of this examine ought to be validated utilizing human microglial cells sooner or later. Many research report species-specific options of microglia [10,11]. Subsequently, findings in rodents have to be validated in human cells. Though this examine [9] confirmed up-regulation of NR4A1 in microglia after stroke in postmortem human brains, it’s unclear whether or not NR4A1 modulates TNF expression through the identical posttranscriptional mechanism in human microglia. Validating this statement in human microglia or microglia derived from induced pluripotent stem cells would considerably enhance the translational potential of this work.
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