The amino acid sensor general control nonderepressible 2 (GCN2) controls TH9 cells and allergic airway inflammation

Abstract

Background: T H 9 cells have emerged as important mediators of allergic airway inflammation. There is evidence that general control nonderepressible 2 (GCN2) affects the immune response under some stress conditions. However, whether GCN2 regulates CD4 1 T-cell differentiation during allergic inflammation remains unknown. Objective: We sought to clarify the regulatory roles of GCN2 in CD4 1 T-cell subset differentiation and its significance in patients with allergic airway inflammation. Methods: The effects of GCN2 in differentiation of T H cell subsets were detected by using the in vitro induction system. GCN2 knockout mice, ovalbumin-induced allergic airway inflammation, and adoptive transfer mouse models were used to determine the significance of GCN2 in T H 9 differentiation and allergic airway inflammation in vivo. RNA sequencing, real-time PCR, Western blotting, and other molecular approaches were used to identify the molecular mechanisms relevant to regulation of GCN2 in T H 9 cell differentiation.

Th9 cells in allergic diseases: A role for the microbiota?

“…Very recently, the expression of peroxisome proliferator-activated receptor γ (PPARγ) was found to be essential for IL-9 production by CD4 T cells, 3 and a novel role for the amino acid sensor general control non-derepressible 2 (GCN2) was discovered in Th9 cell differentiation. 22 Finally, also Smad proteins and Notch signalling were found to influence IL-9 production by binding directly to the IL-9 promoter. In particular, Smad 2 and Smad 4 which are activated by TGF-β signalling, seem to regulate IL-9 gene expression by inducing epigenetic changes at the IL-9 locus, while Notch receptors cooperate with Smad 3 to promote Th9 cell differentiation.…”

“…This binding leads to the formation of a transcription factor complex which consequently inhibits the generation of Treg and Th2 cells, favouring the formation of Th9 cells. Very recently, the expression of peroxisome proliferator‐activated receptor γ (PPARγ) was found to be essential for IL‐9 production by CD4 T cells, and a novel role for the amino acid sensor general control non‐derepressible 2 (GCN2) was discovered in Th9 cell differentiation . Finally, also Smad proteins and Notch signalling were found to influence IL‐9 production by binding directly to the IL‐9 promoter.…”

Amino Acid Metabolism in Lupus

“…It plays a vital role in the control of amino acid metabolism as a response to nutrient deprivation. Gcn2 deficiency significantly inhibits in vitro differentiation of Th9 cells but not Th1, Th2, and Treg cells in mouse model, and it ameliorated allergic airway inflammation in mice ( 62 ). On the other hand, myeloid cell deletion of Gcn2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality ( 63 ).…”

Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress

“…Although general control nonderepressible 2 (GCN2) is a well-known sensor of amino acid availability [ 6 , 7 ], it also plays an important role in other biological processes, including glucose and lipid metabolism [ 8 , 9 , 10 ], the immune response [ 11 , 12 ], memory formation [ 13 ], muscle atrophy [ 14 ] and cell apoptosis [ 15 ]. In the heart, GCN2 deficiency was found to attenuate transverse aortic constriction (TAC) and doxorubicin-induced cardiac dysfunction [ 16 , 17 ].…”