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T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4-/-)-deficient rats in basal and stress conditions.
Bignard, Juliette; Atassi, Fabrice; Claude, Olivier; Ghigna, Maria-Rosa; Mougenot, Nathalie; Abdoulkarim, Bahgat Soilih; Deknuydt, Florence; Gestin, Aurélie; Monceau, Virginie; Montani, David; Nadaud, Sophie; Soubrier, Florent; Perros, Frédéric.
Afiliación
  • Bignard J; UMR_S 1166, Sorbonne Université, INSERM, Paris, France.
  • Atassi F; UMR_S 1166, Sorbonne Université, INSERM, Paris, France.
  • Claude O; UMR_S 1166, Sorbonne Université, INSERM, Paris, France.
  • Ghigna MR; Department of Pathology, Institut Gustave Roussy, Villejuif, France.
  • Mougenot N; UMR_S999, Université Paris-Saclay, INSERM, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
  • Abdoulkarim BS; UMS28, Sorbonne Université, Plateforme d'Expérimentation Cœur, Muscles, Vaisseaux (PECMV), Paris, France.
  • Deknuydt F; UMR_S999, Université Paris-Saclay, INSERM, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
  • Gestin A; Flow Cytometry Core Cyto-ICAN, Institute of Cardiometabolism and Nutrition, Hôpital Pitié-Salpêtrière, Paris, France.
  • Monceau V; Flow Cytometry Core Cyto-ICAN, Institute of Cardiometabolism and Nutrition, Hôpital Pitié-Salpêtrière, Paris, France.
  • Montani D; UMR_S 1166, Sorbonne Université, INSERM, Paris, France.
  • Nadaud S; UMR_S999, Université Paris-Saclay, INSERM, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
  • Soubrier F; Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Assistance Publique Hôpitaux de paris, Le Kremlin Bicêtre, France.
  • Perros F; UMR_S 1166, Sorbonne Université, INSERM, Paris, France.
Am J Physiol Lung Cell Mol Physiol ; 324(5): L609-L624, 2023 05 01.
Article en En | MEDLINE | ID: mdl-36852942
Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2-/- rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2-/- rat lungs revealed increases in two T-cell populations, a LAG3+ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2-/- rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad Veno-Oclusiva Pulmonar / Hipertensión Pulmonar Límite: Animals Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad Veno-Oclusiva Pulmonar / Hipertensión Pulmonar Límite: Animals Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos