tRNA derived fragment (tRF)-3009 participates in modulation of IFN-α-induced CD4+ T cell oxidative phosphorylation in lupus patients

Abstract

Background Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis. Here we aimed to explore aberrant expression of tRFs in CD4+ T cells from patients with systemic lupus erythematosus (SLE) and their potential function in the SLE pathogenesis. Methods First, small RNA sequencing was performed on CD4+ T cells from four SLE patients and three healthy controls (HCs). Candidate tRFs were then validated in CD4+ T cells from 97 SLE patients and their relevant disease controls using qRT-PCR. Then sequencing was used to investigate the profiles of HC-derived CD4+ T cells transfected with tRF-3009. Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4+ T cells with/without IFN-α. Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed. Results We identified 482 differentially expressed tRFs from SLE CD4+ T cells and chose tRF-3009 for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-α levels. In vitro, tRF-3009 over-expressing CD4+ T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways. Interestingly, IFN-α is capable of inducing ROS and ATP production in CD4+ T cells, while knockdown of tRF-3009 reversed this process. Overexpression of tRF-3009 in CD4+ T cells alone was sufficient to upregulate OCR, ROS, and ATP production. Conclusions Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may participate in metabolic modulation of IFN-α-induced CD4+ T cell OXPHOS in lupus.

The Role of Extracellular Vesicles in Systemic Lupus Erythematosus

“…More precisely, Geng et al (2021) showed that tRF-3009 was substantially over-expressed in CD4 + T cells of SLE patients than those of healthy donors. What’s more, tRF-3009 may be involved in SLE pathogenesis by modulation of IFN-α-induced CD4 + T cell oxidative phosphorylation ( Geng et al, 2021 ). As for the EV, Dou et al (2021) revealed that mesenchymal stem cell (MSC)-derived EV tsRNA-21109 inhibited the M1-type polarization of macrophages, offering a promising therapeutic strategy for SLE ( Dou et al, 2021 ).…”

“…In a recent study, Xu et al (2020) found that tRNAs and tsRNAs were significantly differentially expressed in the PBMCs of SLE patients, compared with those of healthy donors, and the targeted genes of the differentially expressed tsRNAs were enriched in the signaling pathway involved in primary immunodeficiency, T cell receptor and Th cell differentiation, suggesting that tRNAs and tsRNAs play important roles in the pathogenesis of SLE (Xu et al, 2020). More precisely, Geng et al (2021) showed that tRF-3009 was substantially over-expressed in CD4 + T cells of SLE patients than those of healthy donors. What's more, tRF-3009 may be involved in SLE pathogenesis by modulation of IFN-α-induced CD4 + T cell oxidative phosphorylation (Geng et al, 2021).…”

Deciphering the tRNA-derived small RNAs: origin, development, and future

“…In GO and KEGG pathway analyses, tsRNAs and their related target genes were established to be enriched in immune response and immune system processes, as well as in signaling pathways such as Th1 and Th2 cell differentiation, T-cell receptor [ 95 ]. tRF-3009 from tRNA-Lue-TAA was first reported by Geng et al, who found that it was highly expressed in CD4 + T cells in SLE and positively correlated with SLE disease activity indices, lupus nephritis, and serum IFNα levels [ 96 ]. Mechanistically, tRF-3009 levels, in tandem with ATP and ROS levels, were elevated by IFNα treatment.…”

“…Mechanistically, tRF-3009 levels, in tandem with ATP and ROS levels, were elevated by IFNα treatment. Upon tRF-3009 knockdown, IFN-α-induced ROS and ATP were inhibited [ 96 ]. These findings imply that tRF-3009 may be involved in SLE development by regulating IFN-α-induced oxidative phosphorylation (OXPHOS) of CD4 + T cells [ 96 ].…”

“…Upon tRF-3009 knockdown, IFN-α-induced ROS and ATP were inhibited [ 96 ]. These findings imply that tRF-3009 may be involved in SLE development by regulating IFN-α-induced oxidative phosphorylation (OXPHOS) of CD4 + T cells [ 96 ]. However, the underlying mechanisms have not been elucidated.…”