Ischemic stroke accounts for approximately 80%–85% of all stroke cases. Although two primary treatments are available for acute cerebral ischemia, reperfusion to ischemic brain tissue may exacerbate cerebral ischemia-reperfusion injury. Increasing evidence indicates that neuroinflammation plays a pivotal role after ischemic stroke, emphasizing the urgent need to understand its underlying mechanisms.

This research, published in the Genes & Diseases journal by a team from Chongqing Medical University and Shanghai Jiao Tong University, investigated the role and mechanism of nuclear factor of activated T cells 5 (NFAT5) in microglia-mediated neuroinflammation following middle cerebral artery occlusion (MCAO) modeling.

Using in vivo (MCAO model) and in vitro (oxygen and glucose deprivation/reoxygenation [OGD/R]) systems, researchers found elevated NFAT5 expression after stroke. Through a microglia-specific gene knockdown strategy via recombinant adeno-associated virus (rAAV), the team selectively suppressed NFAT5 expression in microglia. This inhibition of microglial NFAT5 augmented the synthesis of pro-inflammatory molecules, stimulated microglial activation, facilitated the infiltration of neutrophils, and ultimately triggered neuronal apoptosis.

Previous research by the team reported that the NOD-like receptor pyrin domain-containing 6 (NLRP6), a novel member of the NLR family, aggravated neuroinflammation and brain injury after MCAO modeling. However, in this study, it was demonstrated that NFAT5 could regulate the mRNA and protein levels of NLRP6, thereby modulating the activation of NLRP6 inflammasome. Moreover, NFAT5 was shown to enhance transcriptional activity of the Nlrp6 promoter through the −1527 bp to −1518 bp region of the Nlrp6 promoter. Notably, these findings indicate that NFAT5 plays a role in regulating the mRNA stability of Nlrp6 through the 5'UTR of Nlrp6.

In conclusion, this study offers a novel perspective to elucidate the upstream activation mechanism of the NLRP6 inflammasome. Inhibiting NFAT5 in microglia may represent a promising strategy to mitigate inflammation-induced neuronal apoptosis and reduce brain damage following ischemic stroke.

Reference

Title of Original Paper: Microglial NFAT5 aggravates neuroinflammation via mediating NLRP6 inflammasome in experimental ischemic stroke

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101614

Funding Information:

• The National Natural Science Foundation of China (No. 82071305, 82301512, 82302474)
• Chongqing Postdoctoral Science Foundation (China) (No. cst2023NSCQ-BHX0121)
• Program for Youth Innovation in Future Medicine (Chongqing Medical University, China)
• Chongqing Talent Plan "Contract Program" (China) (No. cstc2022ycjh-bgzxm0057)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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