Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
M, S., Q, G., M, S., A, C., S, M., JA, V., N, V., BJ, D., PD, U., & AAR, T. (2026). Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2531623123
M S, Q G, M S, A C, S M, JA V, et al. Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.. Proceedings of the National Academy of Sciences of the United States of America. 2026; doi: 10.1073/pnas.2531623123
M S, Q G, M S, et al. Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.[J]. Proceedings of the National Academy of Sciences of the United States of America. 2026. DOI: 10.1073/pnas.2531623123.
@article{m2026,
author = {Schwiening M and Gao Q and Southwood M and Crosby A and Moore S and Valer JA and Veale N and Dunmore BJ and Upton PD and Thompson AAR},
title = {Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
doi = {10.1073/pnas.2531623123},
note = {PMID: 42406961},
}
TY - JOUR AU - Schwiening M AU - Gao Q AU - Southwood M AU - Crosby A AU - Moore S AU - Valer JA AU - Veale N AU - Dunmore BJ AU - Upton PD AU - Thompson AAR TI - Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice. T2 - Proceedings of the National Academy of Sciences of the United States of America PY - 2026 DO - 10.1073/pnas.2531623123 AN - PMID:42406961 ER -
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.