| Title: |
Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice. |
| Authors: |
Schwiening, Max; Gao, Qingyue; Southwood, Mark; Crosby, Alexi; Moore, Stephen; Valer, Jose A; Veale, Niki; Dunmore, Benjamin J; Upton, Paul D; Thompson, AA Roger; Morrell, Nicholas W; Marciniak, Stefan J; Soon, Elaine |
| Publisher Information: |
National Academy of Sciences; C.I.M.R. Medicine; //doi.org/10.1073/pnas.2531623123 |
| Publication Year: |
2026 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
GCN2 |
| Description: |
Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/404205; https://doi.org/10.17863/CAM.130899 |
| DOI: |
10.17863/CAM.130899 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/404205; https://doi.org/10.17863/CAM.130899 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.3AB03E67 |
| Database: |
BASE |