Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice

Gab Seok Kim (), Elisabeth Harmon, Manuel C. Gutierrez, Sodam Kim, Lauren Vance, Haven Burrous, Jessica M. Stephenson, Anjali Chauhan, Anik Banerjee, Zachary Wise, Andrea Doan, John Ahn, Ting Wu, Jesus Bautista-Garrido, Juneyoung Lee, Chunfeng Tan, Joo Eun Jung, Louise D. McCullough, Joshua D. Wythe and Sean P. Marrelli ()
Additional contact information
Gab Seok Kim: The University of Texas Health Science Center at Houston
Elisabeth Harmon: The University of Texas Health Science Center at Houston
Manuel C. Gutierrez: Baylor College of Medicine
Sodam Kim: The University of Texas Health Science Center at Houston
Lauren Vance: The University of Texas Health Science Center at Houston
Haven Burrous: The University of Texas Health Science Center at Houston
Jessica M. Stephenson: The University of Texas Health Science Center at Houston
Anjali Chauhan: The University of Texas Health Science Center at Houston
Anik Banerjee: The University of Texas Health Science Center at Houston
Zachary Wise: The University of Texas Health Science Center at Houston
Andrea Doan: The University of Texas Health Science Center at Houston
John Ahn: The University of Texas Health Science Center at Houston
Ting Wu: The University of Texas Health Science Center at Houston
Jesus Bautista-Garrido: The University of Texas Health Science Center at Houston
Juneyoung Lee: The University of Texas Health Science Center at Houston
Chunfeng Tan: The University of Texas Health Science Center at Houston
Joo Eun Jung: The University of Texas Health Science Center at Houston
Louise D. McCullough: The University of Texas Health Science Center at Houston
Joshua D. Wythe: Baylor College of Medicine
Sean P. Marrelli: The University of Texas Health Science Center at Houston

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2a+/- mice) reduced gliosis (microgliosis and astrogliosis), acute and chronic brain injury, and motor function deficits. Together, these findings identify Ifi27l2a as a critical neuroinflammatory mediator in ischemic stroke and provide support for the therapeutic strategy of disrupting Ifi27l2a to attenuate inflammation in the post-stroke brain.

Date: 2025
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DOI: 10.1038/s41467-025-56847-1

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