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Single-nucleus transcriptomic analysis reveals a key role of IRF5 in the brain in regulating neuroinflammation in rats with myocardial infarction
Abstract   Open access   Peer reviewed

Single-nucleus transcriptomic analysis reveals a key role of IRF5 in the brain in regulating neuroinflammation in rats with myocardial infarction

Wanxin Tang, Yang Yu, Jing-Yu Bing, Robert Weiss and Shun-Guang Wei
Journal of Molecular and Cellular Cardiology Plus (Online), Vol.15, 100774
03/2026
DOI: 10.1016/j.jmccpl.2025.100774
url
https://doi.org/10.1016/j.jmccpl.2025.100774View
Published (Version of record) Open Access

Abstract

Introduction: The paraventricular nucleus (PVN) of the hypothalamus is a key autonomic and cardiovascular regulatory center involved in neuroinflammation-driven sympathetic activation and cardiac dysfunction in heart failure (HF). To gain transcriptional insights into the cellular and molecular mechanisms underlying neuroimmune processes that promote sympathetic nervous system and neurohumoral activation in HF, we performed single-nucleus RNA sequencing (snRNA-seq) of the PVN in myocardial infarction (MI)-induced HF rats. Methods: Adult male Sprague Dawley rats underwent coronary artery ligation to induce MI or sham-operated surgery (SHAM). PVN tissues were collected from rats two weeks post-MI for snRNA-seq. The sequencing data underwent alignment, dimensionality reduction, clustering, and marker gene identification to profile individual cell types and gene expression. Gene Set Variation Analysis (GSVA) was used to identify differentially activated inflammatory signaling pathways between HF and control samples. A gene transcription regulatory network (regulon) was constructed to identify key transcription factors associated with inflammation. Results: A total of 16,341 cells were captured and classified into five major cell clusters: neurons, oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, and microglia. Functional analysis highlighted the critical role of microglia in regulating neuroinflammation in MI-induced HF. GSVA identified multiple differentially activated pathways across cell types, with microglia exhibiting significant activation of immune response and cytokine production pathways in HF. Notably, we identified the unique regulon interferon regulatory factor 5 (Irf5) (+) in microglia, which was upregulated in HF and closely associated with pathways regulating neuroinflammation. The regulon Irf5(+) showed a positive correlation with interleukin (IL)-1 production pathways (r = 0.46, p=1.13×10⁻²⁸) and with IL-3/IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathways (r=0.48, p=1.42×10⁻³¹). Immunofluorescent staining confirmed the elevated expression of the core transcription factor Irf5 in PVN microglia in MI-induced HF compared with SHAM. Conclusions: Our snRNA-seq analysis identified novel gene markers, distinct regulons, and differential signaling pathways in individual PVN cell types in MI. Specifically, we identified Irf5(+) as a key microglial regulon contributing to neuroimmune processes and central inflammation in MI-induced HF. Further investigation targeting Irf5 and its downstream effectors may provide valuable insights into the neuroinflammatory mechanisms underlying sympathetic activation-driven cardiac dysfunction and myocardial remodeling in HF.

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