T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4−/−)-deficient rats in basal and stress conditions

生物 人口 炎症 免疫系统 基础(医学) 细胞生物学 免疫学 癌症研究 分子生物学 内分泌学 医学 胰岛素 环境卫生
作者
Juliette Bignard,Fabrice Atassi,Olivier Claude,Maria-Rosa Ghigna,Nathalie Mougenot,Bahgat Soilih Abdoulkarim,Florence Deknuydt,Aurélie Gestin,Virginie Monceau,David Montani,Sophie Nadaud,Florent Soubrier,Frédèric Perros
出处
期刊:American Journal of Physiology-lung Cellular and Molecular Physiology [American Physiological Society]
卷期号:324 (5): L609-L624
标识
DOI:10.1152/ajplung.00460.2021
摘要

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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