{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:19:29Z","timestamp":1785435569499,"version":"3.56.0"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"28","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MR\/R008051\/1"],"award-info":[{"award-number":["MR\/R008051\/1"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,14]]},"abstract":"<jats:p>\n                    Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2\u03b1 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\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    , to mirror\n                    <jats:italic toggle=\"yes\">GCN2<\/jats:italic>\n                    -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\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    -deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    -dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in\n                    <jats:italic toggle=\"yes\">\n                      Gcn2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in\n                    <jats:italic toggle=\"yes\">\n                      Gcn2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mouse fibroblasts and in\n                    <jats:italic toggle=\"yes\">\n                      Gcn2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Using a mitomycin C\u2013induced murine model, genetic deletion of interleukin-6 (\n                    <jats:italic toggle=\"yes\">Il6<\/jats:italic>\n                    ) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in\n                    <jats:italic toggle=\"yes\">\n                      Gcn2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, and\n                    <jats:italic toggle=\"yes\">Il6<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">Gcn2<\/jats:italic>\n                    deficiency\u2013associated and mitomycin C\u2013triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2531623123","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T19:09:56Z","timestamp":1783364996000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-6 is critical in the development of pulmonary vascular disease in\n                    <i>Gcn2-<\/i>\n                    deficient mice"],"prefix":"10.1073","volume":"123","author":[{"given":"Max","family":"Schwiening","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyue","family":"Gao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Southwood","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Cambridge","place":["Cambridge, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical Research Council Toxicology Unit, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexi","family":"Crosby","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Moore","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1184-9491","authenticated-orcid":false,"given":"Jose A.","family":"Valer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4023-7553","authenticated-orcid":false,"given":"Niki","family":"Veale","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Dunmore","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Upton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0717-4551","authenticated-orcid":false,"given":"A. 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