iTreg cells-secreted IL10 alleviates lupus nephritis through inactivating lncRNA HAR1A transcription to suppress SMARCD1-mediated iNOS activation.

Abstract

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.