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Published on: March 17, 2020
The Aberrantly Expressed Nuclear Factor (Erythroid-derived 2)-Like 2 Participates in aGVHD by Modulating the
Xu Chen1,2,3, Yue Zhang1,2,3, Yan Chen1,2,3
1Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Background:
Current investigation indicates that nuclear factor (erythroid-derived 2)-like 2 (NRF2) possesses both proinflammatory and anti-inflammatory capabilities in T cells, yet its exact function in acute graft-versus-host disease (aGVHD) CD4 + T cells remains unexplored.
Methods:
This study aims to determine NRF2 levels within CD4 + T cells of patients with or without aGVHD and analyze the correlation between T-cell receptor activation and NRF2 expression. RNA sequencing was used to detect changes in the expression profile of CD4 + T cells after overexpression of NRF2, and functional enrichment analysis was performed on the sequencing results. Finally, after treating aGVHD CD4 + T cells with NRF2 inhibitor, the expression of related pathway molecules was detected.
Results:
Our findings demonstrated a significant upregulation of NRF2 expression in CD4 + T cells from patients in the aGVHD group compared with patients in the non-aGVHD group, and its expression level is correlated with the severity of aGVHD. Additionally, T-cell receptor activation in CD4 + T cells elevates NRF2 expression. Postactivation of NRF2-inhibited CD4 + T cells, the expression levels of T-cell activation markers were notably lower than those in non-NRF2-inhibited CD4 + T cells. Sequencing analysis identified 904 genes that changed after NRF2 overexpression. These genes were categorized into 288 gene subsets, encompassing pathways such as T-cell receptor signaling transduction, Janus kinase 1/signal transducer and activator of transcription 1 (JAK1-STAT1) signaling, T helper cell 17 (Th17) cell differentiation, etc. Ultimately, treating CD4 + T cells of aGVHD patients with an NRF2 inhibitor led to a significant downregulation of JAK1-STAT1 signaling and Th17 cells.
Conclusions:
Elevated NRF2 expression in CD4 + T cells of patients with aGVHD initiates and exacerbates aGVHD by potentiating T-cell activation, amplifying JAK1/STAT1 signaling, and instigating Th17/regulatory T-cell ratio imbalance.
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