Although accumulated evidence has reported that lncRNAs have an essential role in SLE patients, such as lncRNA NONHSAT101022.2 and lncRNA IL21-AS1 in blood samples (18, 19), none of them has investigated the role of lncRNAs in child-onset SLE. Approximately 20% of SLE patients with childhood onset exhibit higher disease activity, faster development of organ system damage, and more aggressive therapeutic requirements compared to adult-onset (20, 21). In adults, very rare (about 3%) SLE patients to suffer disease caused by genetic risk, while in children, this number rises to 7% (22, 23). By now, the investigations of biomarkers and treatment in SLE are mostly based on studies in adult-onset cohorts, further investigations for children are urgently required.
In this study, the expression profiles of lncRNAs and mRNAs were assessed in the peripheral blood of LN patients and healthy donors by small RNA sequencing, followed by RT-PCR. Additionally, bioinformatics analysis was used to reveal the predicted biological functions and significant pathways of these altered mRNAs.
NOD-like receptors (NLRs) pathway activation is a well-known mechanism that plays essential roles in innate immune response (24) and is involved in the pathogenesis and development of various autoimmune diseases, including SLE (25). A study reported that bacterial exposure could stimulate the NOD2 expression in monocytes of SLE patients compared to that in the healthy group, resulting in the production of proinflammatory cytokines by PBMCs (26). Accumulating evidence has shown that the expression of NLRP3, the subfamily of NLRs, is hyperactivated in SLE patients and is associated with the disease activity (27). In contrast, two studies showed that NLRP3 inflammasome levels were significantly decreased in SLE patients and negatively correlated with disease severity (28, 29). These contradictory results may be explained by the inhibitory effect of overactivated T cells and the chaotic activity of type I interferon in patients. In this study, we identified the NLR signaling pathway as a leading enriched pathway associated with the altered lncRNAs (Fig. 3C), which suggested that these lncRNAs might have regulatory functions in the pathogenesis of SLE.
It has been reported that Th17 immune responses and the related cytokines IL-17 play important regulatory roles in tissue inflammation and autoimmunity (30). In LN, Th17/IL-17 axis was involved in repetitive tissue damage and maladaptive repair, resulting in renal fibrosis and loss of renal function. The imbalanced polarization of Th17/Treg cells was found in LN patients, which is the overactivation of Th17/IL-17 axis and the suppression or dysfunction of Treg cells (31). Terui et al. reported that microbiota exposure could trigger Th17/IL-17 immune response, leading to SLE-like autoimmune inflammation in mice models (32). In addition, emerging studies reported that imbalanced Th1/Th2, Th1/Th17, and Th17/Treg profiles were detected in SLE patients compared to healthy controls (33–35). Various cytokines are present in SLE patients due to the complexity of SLE pathogenesis. IL-17 signaling pathway and Th1/Th2 cell differentiation are also enriched pathways of the target genes of the altered lncRNAs in this study, it is interesting to explore the potential roles of these lncRNAs associated with the polarization of T cells.
This is an innovative study to report the expression profiles of lncRNAs from human clinical samples of child-onset LN patients, which detected a total of 502 altered lncRNAs compared to the age-matched healthy control. Moreover, through bioinformatics analysis, we predicted the target genes of the significantly changed lncRNAs, as well as the potential biological functions and possible involved pathways that might contribute to LN pathogenesis.
There are several limitations to this study. The renal biopsy in patients was not performed to assess the clear pathologic classification of LN. Second, based on the complexity of the disease, it is necessary to increase the number of included subjects to validate the altered lncRNAs. Last, further functional assessment of the identified lncRNAs is lacking.
In conclusion, the present study reported the altered expression profiles of lncRNAs in child-onset LN patients and predicted potential target genes that might be involved in pathogenesis and development. Therefore, these lncRNAs could be promising biomarkers to identify LN disease, as well as novel therapeutic targets for patients with LN.