NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker

Abstract

BackgroundSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with various clinical manifestations. MicroRNAs (miRNAs) and immunometabolism are recognized as key elements in SLE pathogenesis; however, the relationship between miRNAs in peripheral blood mononuclear cells (PBMCs) and metabolism in SLE remains unclear.MethodsWe detected PBMC miRNA and mRNA profiles from 3 pooled SLE patients and 3 healthy controls (HCs) using next-generation sequencing, predicted miRNA targets in dysregulated mRNAs, predicted functions and interactions of differentially expressed genes using bioinformatics analysis, validated candidate miRNAs using qRT-PCR, and investigated the association between the expression of candidate miRNAs and SLE clinical characteristics. Moreover, we validated the direct and transcriptional regulatory effect of NovelmiRNA-25 on adenosine monophosphate deaminase 2 (AMPD2) using a dual-luciferase reporter assay and western blot and confirmed AMPD2 mRNA and protein expression in PBMCs using qRT-PCR and western blot, respectively.ResultsMultilayer integrative analysis of microRNA and mRNA regulation showed that 10 miRNAs were down-regulated and 19 miRNAs were up-regulated in SLE patient PBMCs compared with HCs. Bioinformatics analysis of regulatory networks between miRNAs and mRNAs showed that 19 miRNAs were related to metabolic processes. Two candidate miRNAs, NovelmiRNA-25 and miR-1273h-5p, which were significantly increased in the PBMCs of SLE patients (P < 0.05), represented diagnostic biomarkers with sensitivities of 94.74% and 89.47%, respectively (area under the curve = 0.574 and 0.788, respectively). NovelmiRNA-25 expression in PBMCs was associated with disease activity in SLE patients, in both active and stable groups (P < 0.05). NovelmiRNA-25 overexpression downregulated AMPD2 expression in HEK293T cells through direct targeting of the AMPD2 3ʹUTR (P < 0.01), while inhibition of NovelmiRNA-25 activity led to increased AMPD2 expression (P < 0.01). NovelmiRNA-25 overexpression also downregulated AMPD2 protein expression in HEK293T cells; AMPD2 protein expression in SLE patient PBMCs was decreased. Our results show that differentially expressed miRNAs play an important role in SLE.ConclusionsOur data demonstrate a novel mechanism in SLE development that involves the targeting of AMPD2 expression by NovelmiRNA-25. miRNAs may serve as novel biomarkers for the diagnosis and evaluation of disease activity of SLE and represent potential therapeutic targets for this disease.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1739-5) contains supplementary material, which is available to authorized users.

Diagnostic significance of circulating miRNAs in systemic lupus erythematosus

“…However, five articles were excluded by reading their complete articles due to article types, seven studies lacked available data to construct a 2×2 table, and four articles lacked a comparison between SLE patients and healthy controls. Finally, 17 studies [17][18][19][20][21][31][32][33][34][35][36][37][38][39][40][41][42] were included in the meta-analysis. The process of study selection was illustrated in Fig 1. Except the study of Zununi Vahed et al [42] is a cross-sectional trial, all others are prospective trials.…”

“…Additionally, the ideal time for specimen acquisition was before treatment. Unfortunately, only two of the studies [17,31] involved in our meta-analysis indicated that blood samples were collected before treatment, while six studies [20,33,37,39,40,42] did not clarify when the specimens were obtained, five studies [18,19,21,36,41] stated that samples were collected during the period of treatments, and four articles [32,34,35,38] indicated that the time for specimen collection was after the patients had stopped treatments for a period of time. Thus, these differences in patient and blood collection time could cause inevitable bias to our results.…”

MALAT1 is involved in type I IFNs-mediated systemic lupus erythematosus by up-regulating OAS2, OAS3, and OASL

“…Systemic lupus erythematosus (SLE) is an autoimmune disease and its prevalence varies from approximately 20 to 70 per 100,000 people per year, and incidence rates for women are approximately ten times higher than those for men worldwide (1,2). More than 80% of patients with SLE present clinical manifestations such as nephritis, multisystem organ failure, or central nervous system disease.…”

Dysbiosis in Peripheral Blood Mononuclear Cell Virome Associated With Systemic Lupus Erythematosus

“…Functional analyses further identified cellular process, metabolic process, regulation of signal transduction, and cell surface receptor signaling pathway to be important in the development of autoimmune diseases. In a previous research, we showed that mRNAs differentially expressed between SLE patients and HCs in PBMCs were also enriched in cellular process, metabolic process, and Wnt signaling pathway (Guo et al, 2018a). Immunometabolism in SLE involves dysregulation in many immune cells, including CD4+ T cells, dendritic cells, macrophages, and neutrophils (Morel, 2017).…”