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Respiratory Research
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Open Access 01-12-2024 | Research

Intestinal IFNα4 promotes 15-HETE diet-induced pulmonary hypertension

Authors: Grégoire Ruffenach, Lejla Medzikovic, Laila Aryan, Wasila Sun, Long Lertpanit, Ellen O’Connor, Ateyeh Dehghanitafti, Mohammad Reza Hatamnejad, Min Li, Srinivasa T. Reddy, Mansoureh Eghbali

Published in: Respiratory Research | Issue 1/2024

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Abstract

Objectives

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of the pulmonary vascular bed leading to elevation of the pulmonary arterial pressure. Oxidized fatty acids, such as hydroxyeicosatetraenoic acids (HETEs), play a critical role in PAH. We have previously established that dietary supplementation of 15-HETE is sufficient to cause PH in mice, suggesting a role for the gut-lung axis. However, the mechanisms are not known.

Approach

Analysis of RNA-seq data obtained from the lungs and intestines of mice on 15-HETE diet together with transcriptomic data from PAH patient lungs identified IFN inducible protein 44 (IFI44) as the only gene significantly upregulated in mice and humans. We demonstrate that IFI44 is also significantly increased in PBMCs from PAH patients. In mice, 15-HETE diet enhances IFI44 and its inducer IFN⍺4 expression sequentially in the intestine first and then in the lungs. IFI44 expression in PAH is highly correlated with expression of Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), which is upregulated in CD8 cells in PH lungs of both mice and humans. We show that IFNα4 produced by intestinal epithelial cells facilitates IFI44 expression in CD8 cells. Finally, we demonstrate that IFN receptor 1-KO in mice do not develop PH on 15-HETE diet. In addition, silencing IFI44 expression in the lungs of mice on 15-HETE diet prevents the development of PH and is associated with significantly lower expression of IFI44 and TRAIL in CD8 cells in the lungs.

Conclusion

Our data reveal a novel gut-lung axis driven by 15-HETE in PH.
Appendix
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Metadata
Title
Intestinal IFNα4 promotes 15-HETE diet-induced pulmonary hypertension
Authors
Grégoire Ruffenach
Lejla Medzikovic
Laila Aryan
Wasila Sun
Long Lertpanit
Ellen O’Connor
Ateyeh Dehghanitafti
Mohammad Reza Hatamnejad
Min Li
Srinivasa T. Reddy
Mansoureh Eghbali
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2024
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-024-03046-z

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