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

Author

Listed:
  • Gab Seok Kim

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Elisabeth Harmon

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Manuel C. Gutierrez

    (Baylor College of Medicine)

  • Sodam Kim

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Lauren Vance

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Haven Burrous

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Jessica M. Stephenson

    (The University of Texas Health Science Center at Houston)

  • Anjali Chauhan

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Anik Banerjee

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Zachary Wise

    (The University of Texas Health Science Center at Houston)

  • Andrea Doan

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • John Ahn

    (The University of Texas Health Science Center at Houston)

  • Ting Wu

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Jesus Bautista-Garrido

    (The University of Texas Health Science Center at Houston)

  • Juneyoung Lee

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Chunfeng Tan

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Joo Eun Jung

    (The University of Texas Health Science Center at Houston)

  • Louise D. McCullough

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

  • Joshua D. Wythe

    (Baylor College of Medicine
    Baylor College of Medicine
    University of Virginia School of Medicine
    University of Virginia School of Medicine)

  • Sean P. Marrelli

    (The University of Texas Health Science Center at Houston
    BRAINS Research Laboratories at UTHealth)

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.

Suggested Citation

  • 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, 2025. "Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56847-1
    DOI: 10.1038/s41467-025-56847-1
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    References listed on IDEAS

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    1. Natalia Ochocka & Pawel Segit & Kacper Adam Walentynowicz & Kamil Wojnicki & Salwador Cyranowski & Julian Swatler & Jakub Mieczkowski & Bozena Kaminska, 2021. "Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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