Intestinal IFNα4 promotes 15-HETE diet-induced pulmonary hypertension

Area of Science:

• Pulmonary vascular remodeling
• Gut-lung axis in disease pathogenesis
• Inflammatory signaling pathways

Background:

• Pulmonary arterial hypertension (PAH) involves pulmonary vascular remodeling and elevated pressure.
• Oxidized fatty acids, like 15-hydroxyeicosatetraenoic acid (15-HETE), are implicated in PAH.
• Dietary 15-HETE induces pulmonary hypertension (PH) in mice, suggesting a gut-lung axis, but mechanisms remain unclear.

Purpose of the Study:

• To elucidate the mechanisms of the gut-lung axis in 15-HETE-induced pulmonary arterial hypertension.
• To identify key molecular players involved in this pathway.
• To investigate the role of IFN-inducible protein 44 (IFI44) and its regulators.

Main Methods:

• Comparative transcriptomic analysis of lung and intestinal RNA-seq data from mice on a 15-HETE diet and human PAH patient lung data.
• Analysis of peripheral blood mononuclear cells (PBMCs) from PAH patients.
• Investigated the sequential expression of IFI44 and IFNα4 in the intestine and lungs.
• Examined the correlation between IFI44 and Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) in CD8 cells.
• Utilized IFN receptor 1-knockout (KO) mice and IFI44 gene silencing models.

Main Results:

• IFI44 was identified as a key gene upregulated in both mice and humans with PAH.
• 15-HETE diet increased IFI44 and IFNα4 expression sequentially in the intestine, then lungs.
• IFI44 expression correlated with TRAIL upregulation in CD8 cells in both mouse and human PH lungs.
• IFNα4 from intestinal cells promoted IFI44 expression in CD8 cells.
• IFN receptor 1-KO mice did not develop PH on a 15-HETE diet.
• IFI44 silencing prevented PH development and reduced IFI44 and TRAIL in lung CD8 cells.

Conclusions:

• A novel gut-lung axis driven by 15-HETE contributes to pulmonary arterial hypertension.
• The pathway involves IFNα4-mediated induction of IFI44 in CD8 cells, leading to TRAIL upregulation.
• Targeting this gut-lung axis may offer new therapeutic strategies for PAH.