Key result
Targeting IL-27 mitigates pressure-overload-induced cardiac inflammation, fibrosis, and dysfunction in mice.
Why the study?
Heightened interleukin-27 (IL-27) activity during sterile inflammation can induce severe tissue damage, yet its specific function in regulating systolic overload-induced cardiac inflammation, oxidative stress, and heart failure pathogenesis remained unknown.
Does modulation of the IL-27 signaling axis affect systolic overload-induced cardiac inflammation, oxidative stress, fibrosis, and heart failure progression in mice?
Does modulation of the IL-27 signaling axis affect systolic overload-induced cardiac inflammation, oxidative stress, fibrosis, and heart failure progression in mice?
Identifies IL-27 as a critical pathogenic driver of pressure overload-induced cardiac inflammation, fibrosis, and heart failure in mice, suggesting potential as a therapeutic target.
Answers are grounded in this paper and cite their sources.
IL-27 neutralization attenuates TAC-induced HF in mice; hypothesis-generating for therapeutic targeting in human pressure-overload cardiomyopathy.
BACKGROUND The interleukin-27 (IL-27) signaling axis plays a critical role in immunity and systemic metabolism. While it initiates potent pro-inflammatory responses against cancer and infection, heightened IL-27 activity during sterile inflammation can induce severe tissue damage. However, the specific function of IL-27 in regulating systolic overload-induced cardiac inflammation, oxidative stress, and heart failure (HF) pathogenesis remains unknown. METHODS We investigated the effects of genetic IL-27 receptor alpha (IL-27Rα) deficiency (IL-27Rα knockout), pharmacological IL-27 neutralization, and recombinant IL-27 administration on transverse aortic constriction (TAC)-induced HF in mice. RESULTS Cardiac IL-27 expression was significantly elevated in murine HF tissues. Global genetic ablation of IL-27Rα significantly suppressed TAC-induced cardiac inflammation, oxidative stress, fibrosis, hypertrophy, dysfunction, and mortality. Corroborating these protective effects, transcriptomic analysis (RNA-seq) revealed that collagen-containing extracellular matrix and extracellular regions were the top cellular components affected in IL-27Rα knockout mice following TAC. Specifically, IL-27Rα deficiency drastically suppressed pathways driving extracellular matrix remodeling, immune responses, and antigen presentation, while significantly downregulating networks governing systemic inflammation and oxidative stress. Furthermore, pharmacological neutralization of IL-27 effectively attenuated TAC-induced left ventricular (LV) leukocyte infiltration, oxidative stress, fibrosis, and dysfunction. Conversely, administration of recombinant mouse IL-27 exacerbated the TAC-induced cardiac accumulation of multiple immune cell subsets, oxidative stress, fibrosis, cardiomyocyte hypertrophy, and overall HF progression. CONCLUSIONS Our findings demonstrate that IL-27 acts as a critical pathogenic driver of cardiac inflammation, oxidative stress, and HF development by modulating both immune cell activation and extracellular matrix remodeling following systolic overload.
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Niu et al. (2026) studied Transverse aortic constriction (TAC)-induced heart failure in mice. Genetic IL-27Rα deficiency (knockout), pharmacological IL-27 neutralization, and recombinant mouse IL-27 administration vs. Wild-type or untreated/vehicle control mice undergoing TAC was evaluated on TAC-induced cardiac inflammation, oxidative stress, fibrosis, hypertrophy, left ventricular dysfunction, and mortality. Genetic IL-27Rα ablation and pharmacological IL-27 neutralization suppressed TAC-induced cardiac inflammation, oxidative stress, fibrosis, and HF dysfunction in mice, whereas recombinant IL-27 exacerbated them.
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