Associate Investigator National Health Research Institutes, United States
Disclosure(s):
Huai-Chia Chuang, PhD: No financial relationships to disclose
Introduction/Rationale: Systemic lupus erythematosus (SLE) is a chronic and incurable autoimmune disease. The protein levels of the TCR negative regulator DUSP22 (dual-specificity phosphatase 22) are significantly decreased in T cells from 55.8% SLE patients. Downregulation of DUSP22 in T cells results in hyperactivation of the kinase Lck, leading to T-cell-mediated inflammation and autoimmune diseases. The diagnostic power of DUSP22 downregulation in T cells for active lupus nephritis is even higher than those of existing clinical parameters (including serum anti-dsDNA antibody, C3, and C4 levels). The mechanism of DUSP22 downregulation in SLE T cells is unclear. Dysregulation of lncRNAs is associated with the progression of many diseases; however, the roles of T-cell lncRNAs in SLE pathogenesis remain unclear.
Methods: To identify the pathogenic T-cell lncRNAs of SLE (lncSLEs) that regulate DUSP22 levels in SLE T cells, RNAs isolated from T cells of SLE patients and healthy controls were subjected to transcriptomics.
Results: Forty six lncRNAs (lncSLE-1 to lncSLE-46) were differentially expressed in T cells of SLE patients. Among these 46 lncSLEs, 37 lncSLEs were significantly upregulated, and 9 lncSLEs were significantly downregulated. Interestingly, one downregulated novel lncRNA, lncSLE-3, showed a high calculated binding score to DUSP22 mRNA. Overexpression of lncSLE-3 induced DUSP22 mRNA and protein levels in Jurkat T cells. Moreover, sequence analysis showed that 6 miRNAs had putative binding sites on both DUSP22 mRNA and lncSLE-3. Overexpression of the two top-ranked miRNAs (miRNA-1 and miRNA-2) resulted in downregulation of DUSP22 mRNA and protein levels.
Conclusion: These results suggest that lncSLE-3 downregulation in SLE T cells induces miRNA-mediated DUSP22 degradation, contributing to T-cell-mediated autoimmune disease. Restoration of DUSP22 expression by overexpressing lncSLE-3 in T cells may be a novel therapeutic strategy for SLE nephritis.
