IL27 exerts a powerful effect on systolic overload-induced cardiac inflammation, fibrosis, and heart failure development
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BACKGROUND
Interleukin-27 (IL-27) is a heterodimeric cytokine that serves as a bifunctional rheostat rather than an inherently pro- or anti-inflammatory signaling protein. However, the specific role of IL-27 in regulating systolic overload-induced cardiac inflammation and heart failure (HF) pathogenesis remains unknown.
METHODS
We investigated the effects of genetic IL-27 receptor deficiency (IL-27Rα knockout), pharmacological IL-27 blockade, and recombinant IL-27 administration on transverse aortic constriction (TAC)-induced HF in mice.
RESULTS
Cardiac IL-27 expression was significantly elevated in both murine and human HF tissues. The global genetic ablation of the IL-27 receptor (IL-27Rα) significantly suppressed TAC-induced cardiac inflammation, fibrosis, hypertrophy, HF progression, and mortality. Corroborating these protective effects, transcriptomic analysis (RNA-seq) revealed that IL-27Rα deficiency drastically suppressed pathways driving immune responses and antigen presentation, alongside the significant downregulation of networks governing systemic inflammation, pathogen infection, and extracellular matrix remodeling. Furthermore, pharmacological neutralization of IL-27 effectively attenuated TAC-induced left ventricular dysfunction, chamber dilation, myocardial hypertrophy, fibrosis, and leukocyte infiltration. Conversely, the administration of recombinant mouse IL-27 exacerbated the TAC-induced cardiac accumulation of multiple immune cell subsets, resulting in worsened cardiac fibrosis, cardiomyocyte hypertrophy, and overall HF progression.
CONCLUSIONS
Our findings demonstrate that IL-27 acts as a critical pathogenic driver of cardiac inflammation and HF development by modulating both cardiac immune cells (predominantly T cells) and non-immune cells, highlighting the IL-27 signaling axis as a promising therapeutic target.
