Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension

Rao, R. J.; Yang, J.; Jiang, S.; El Khoury, W.; Hafeez, N.; Okawa, S.; Tai, Y. Y.; Tang, Y.; Al Aaraj, Y.; Sembrat, J.; Chan, S. Y.

doi:10.1101/2024.09.19.613988

bioRxiv · 10.1101/2024.09.19.613988

Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension

Rao, R. J.·Yang, J.·Jiang, S.·El Khoury, W.·Hafeez, N.·Okawa, S.·Tai, Y. Y.·Tang, Y.·Al Aaraj, Y.·Sembrat, J.·Chan, S. Y.

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Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH is poorly understood. Here, we demonstrate a role for interferon inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, utilizing human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1{beta} up-regulates IFI16 expression, inducing proinflammatory cytokine up-regulation and cellular apoptosis. IFI16 mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of IFI16. Additionally, m6A levels are increased in the peripheral blood mononuclear cells of PAH patients compared to control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension.

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Rao, R. J., Yang, J., Jiang, S., El Khoury, W., Hafeez, N., Okawa, S., Tai, Y. Y., Tang, Y., Al Aaraj, Y., Sembrat, J., Chan, S. Y.. 2024-09-20. Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension. https://doi.org/10.1101/2024.09.19.613988

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