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Lupus nephritis (LN) is a highly prevalent complication of systemic lupus erythematosus (SLE). Long non-coding RNAs (lncRNAs) are essential modulators in multiple types of human diseases, including LN. In the current study, we searched on online GEO database to select out lncRNAs that were differentially expressed in blood samples of LN patients. Through further RT-qPCR analysis, we found that lncRNA Highly Accelerated Region 1 A (HAR1A) is most significantly upregulated in blood samples of LN patients. Functionally, we detected that overexpression of HAR1A could aggravate LPS-induced injury and inflammation. According to the results of bioinformatics analysis and mechanism experiments, we determined that HAR1A binds with miR-149-3p to upregulate SMARCD1 through competing endogenous RNA (ceRNA) mechanism. It has been proven that iNOS is an inflammation inducer. Here, we found that HAR1A/miR-149-3p/SMARCD1 upregulates iNOS expression through enhancing H3K27ac level in iNOS promoter. Previously, we proved that CD8+CD103+ iTreg cells could alleviate glomerular endothelial cell injury. Moreover, we demonstrated that CD8 + CD103+ iTreg cells-secreted IL-10 downregulated HAR1A expression by impeding NF-κB pathway activation. In conclusion, this study provides evidences revealing a novel molecular pathway blocked by CD8+CD103+ iTreg cells in LN. [ABSTRACT FROM AUTHOR]

Objectives We previously reported that ex vivo TGF-β and IL-2–induced CD8+CD103+ regulatory T cells (CD8+CD103+ iTregs) displayed similar immunosuppressive effect and therapeutic function on lupus mice nephritis to that of CD4+Foxp3+ Tregs. In view of the important role of glomerular endothelial cell (GEC) injury in inflammatory processes in SLE, this study aimed to investigate the nature and mechanism of CD8+CD103+ iTregs–mediated amelioration of LN by attenuating GEC injury. Methods Treg cells from patients with SLE and from healthy controls were characterized by flow cytometry analysis. The expression of pro-inflammatory mediators and VEGF were analysed in healthy controls, patients with SLE and MRL /lpr mice by ELISA, western blot, and real-time quantitative RT-PCR (qRT-PCR). Typical lesions of diffuse proliferative LN were observed in MRL /lpr mice through the use of haematoxylin and eosin, Masson, periodic acid–Schiff, periodic acid–Schiff methenamine, transmission electron microscopy and IF microscopy. Angiogenesis was analysed in GECs by cell investigating proliferation, migration, and tube formation. Results The results revealed that the frequency of Treg cells was inversely correlated with the expression of VCAM-1 and ICAM-1 in patients with SLE. Furthermore, adoptive transfer of CD8+CD103+ iTregs to MRL /lpr mice was associated with decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, and lowered renal deposition of IgG/C3. We further found that CD8+CD103+ iTregs not only suppressed the expression of pro-inflammatory mediators but also attenuated GEC injury by promoting angiogenesis. Conclusion Our study has identified the role of CD8+CD103+ iTregs on attenuating GEC injury and provided a possible application of this new iTregs subset in lupus nephritis and other autoimmune diseases. [ABSTRACT FROM AUTHOR]