Elevated expression of miR-142-3p is related to the pro-inflammatory function of monocyte-derived dendritic cells in SLE

Abstract

BackgroundRecent studies have shown that alterations in the function of dendritic cells (DCs) are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of the alteration remains unclear.MethodsWe cultured monocyte-derived DCs (moDCs) in vitro and examined the cytokines and chemokines in the supernatants of moDCs in negative controls (NC) and SLE patients in active phase. We then profiled microRNAs (miRNAs) of LPS-stimulated moDCs in SLE patients and used real-time PCR to verify the differentially expressed miRNAs. A lentiviral construct was used to overexpress the level of miR-142-3p in moDCs of NC. We examined the cytokines and chemokines in the supernatants of moDCs overexpressing miR-142-3p and used Transwell test, flow cytometric analysis and cell proliferation to observe the impact on CD4+ T cells in moDC-CD4+T cell co-culture.ResultsmoDCs in patients with SLE secreted increased level of IL-6, CCL2 and CCL5, with attraction of more CD4+ T cells compared with NC. We found 18 differentially expressed microRNAs in moDCs of SLE patients by microarray, and target gene prediction showed some target genes of differentially expressed miRNAs were involved in cytokine regulation. miR-142-3p was verified among the highly expressed miRNAs in the SLE group and overexpressing miR-142-3p in moDCs of the NC group caused an increase of SLE-related cytokines, such as CCL2, CCL5, CXCL8, IL-6 and TNF-α. Moreover, moDCs overexpressed with miR-142-3p resulted in attraction of an increased number of CD4+ T cells and in suppression of the proportion of Tregs in DC-CD4+T cell co-culture whereas the proliferation of CD4+T cells was not altered.ConclusionsThe results demonstrated a role for miR-142-3p in regulating the pro-inflammatory function of moDCs in the pathogenesis of SLE. These findings suggested that miR-142-3p could serve as a novel therapeutic target for the treatment of SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1158-z) contains supplementary material, which is available to authorized users.

MicroRNA‐mediated regulation of T helper type 17/regulatory T‐cell balance in autoimmune disease

“…The miRNAs could modulate the balance of Th17/Treg in a cell non-autonomous way, that is, through targeting factors important for Th17 and Treg cell development in non-T cells. miR-363, 51 miR-142-3p 61 and miR-223 49 were dysregulated in DCs and could promote Th17 cell differentiation during the pathogenesis of autoimmune diseases. miR-363 suppresses the expression of integrin av, which is an important positive regulator of TGF-b activation.…”

Role of microRNAs in the Regulation of Dendritic Cell Generation and Function

“…Indeed, in the last few years, miRNAs have emerged as key regulators of inflammation, promoting or suppressing this DC-mediated process [72] (Table 2). Secretion of pro-inflammatory cytokines involved in Crohn's disease [84] miR-142-3p Activation of adaptive immune response mediated by APC [85][86][87] miR-10 NOD2 Maintenance of intestinal homeostasis [88,89] miR-107 Maintenance of intestinal homeostasis Influence the immune response to microbiota [90] miR-223 C/EBPβ Maintenance of homeostasis of the intestinal environment [91] The innate and adaptive responses are highly regulated by cellular and molecular mechanisms through the regulation of the gene expression of specific factors in the cells involved. For this reason, the contribution of miRNAs to inflammatory processes has been amply investigated.…”

“…This was confirmed by miRNA expression analysis in the pathogenesis of systemic lupus erythematosus (SLE). In fact, the overexpression of miR-142-3p in mo-DCs and cytokines, such as CCL2, CCL5, CXCL8, IL-6, and TNF-α, result in increases in the inflammatory context [85]. Moreover, miR-142-3p, together with miR-24 and miR-30b, can regulate the activation of adaptive immune responses guided by APCs [86,87].…”

MiR-142-3p Enhances Cell Viability and Inhibits Apoptosis by Targeting CDKN1B and TIMP3 Following Sciatic Nerve Injury

“…Recently, miR-142-3p has been reported to be associated with neuronal diseases. miR-142-3p is the key therapeutic target for repairing sensory function via adenylyl cyclase 9 (AC9) [29]; miR-142-3p in regulating the pro-inflammatory function of moDCs in the pathogenesis of systemic lupus erythematosus (SLE) [30]; miR-142-3p was downregulated in Tuberous sclerosis (TSC) [31]; miR-142-3p was down-regulated in secondary progressive multiple sclerosis (SPMS) [32]; miR-142-3p were aberrantly expressed in peripheral blood mononuclear cells from relapsing remitting multiple sclerosis (RRMS) patients [33]. Although these studies have suggested that miR-142-3p is involved in neuronal development, it remains unclear whether miR-142-3p also plays a role in neuronal regeneration.…”