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Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with a heterogeneous course and varying degrees of severity and organ damage; thus, there is increasing interest in identifying biomarkers for SLE. In this study we correlated the combined expression level of multiple interferon-inducible chemokines with disease activity, degree of organ damage and clinical features in SLE, and we investigated their roles as biomarkers., Methods: Peripheral blood cells obtained from 67 patients with SLE patients, 20 patients with rheumatoid arthritis (RA) and 23 healthy donors were subjected to real-time PCR in order to measure the transcriptional levels of seven interferon-inducible chemokines (RANTES, MCP-1, CCL19, MIG, IP-10, CXCL11, and IL-8). The data were used to calculate a chemokine score for each participant, after which comparisons were performed between various groups of SLE patients and control individuals., Results: Chemokine scores were significantly elevated in SLE patients versus RA patients and healthy donors (P = 0.012 and P = 0.002, respectively). Chemokine scores were correlated positively with SLE Disease Activity Index 2000 scores (P = 0.005) and negatively with C3 levels (P < 0.001). Compared with patients without lupus nephritis and those with inactive lupus nephritis, chemokine scores were elevated in patients with active lupus nephritis, especially when their daily prednisone dosage was under 30 mg (P = 0.002 and P = 0.014, respectively). Elevated chemokine scores were also associated with the presence of cumulative organ damage (Systemic Lupus International Collaborating Clinics/American Society of Rheumatology Damage Index >or= 1; P = 0.010) and the occurrence of anti-Sm or anti-RNP autoantibodies (both P = 0.021)., Conclusions: The combined transcription level of interferon-inducible chemokines in peripheral blood leucocytes is closely associated with disease activity, degree of organ damage, and specific autoantibody patterns in SLE. The chemokine score may serve as a new biomarker for active and severe disease in SLE.

Objective: To investigate the expression levels of interferon (IFN)-alpha, -beta, -omega and -gamma genes and proteins in the peripheral blood of patients with systemic lupus erythematosus (SLE), and to evaluate any possible connections between these expression levels with clinical features., Methods: 144 SLE patients, 27 non-SLE patients with rheumatisms and 59 normal controls were recruited for the research, and all subjects were drawn blood to isolate plasma and elute total RNA. SYBR Green Dye based real-time quantitative PCR method was used to compare the expression levels of 4 IFNs in patients with SLE and those in the controls. The significance for the correlation of these expression levels and disease activity and specificity was studied., Results: (1) mRNA expression levels of all 4 IFNs in SLE patients were remarkably lower than those observed in normal controls (P < 0.01 in all); IFN-alpha expression levels in SLE patients were increased than those observed in non-SLE group (P < 0.01). (2) The expression levels of all 4 IFNs in active SLE patients were similar to those observed in inactive SLE patients (P > 0.05 in all), and expression levels of all 4 IFNs in patients with SLE were not correlated with involvements of kidney, lung, brain, blood. (3) IFN score in SLE patients was remarkably lower than that observed in normal controls (P < 0.01). (4) The expression levels of all 4 IFNs in both SLE patients and normal controls were positively correlated with each other (P < 0.01 in all). (5) Protein levels of IFN-alpha, IFN-beta and IFN-omega in patients with SLE were similar to those observed in normal group (P > 0.05 in all), protein level of IFN-alpha in active SLE group was apparently elevated than in inactive SLE group (P < 0.01), and protein level of IFN-gamma has a trend to increase in SLE group than in normal group., Conclusions: Decreased expression levels of IFN-alpha, -beta, -omega and -gamma have implicated significance in the determination of SLE disease specificity, of which IFN-alpha is the best. Lower expression level of IFN score has also significance in the determination of SLE disease specificity. Higher protein level of IFN-alpha is helpful to judging SLE disease activity.

Objective: The diminished expression of microRNA‐146a (miR‐146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE‐affected enhancers responsible for modulating miR‐146a expression. Additionally, we aim to elucidate the mechanisms by which these enhancers influence the contribution of miR‐146a to the activation of the interferon pathway. Methods: Circular chromosome conformation capture sequencing and epigenomic profiles were applied to identify candidate enhancers of miR‐146a. CRISPR activation was performed to screen functional enhancers. Differential analysis of chromatin accessibility was used to identify SLE‐dysregulated enhancers, and the mechanism underlying enhancer dysfunction was investigated by analyzing transcription factor binding. The therapeutic value of a lupus‐related enhancer was further evaluated by targeting it in the peripheral blood mononuclear cells (PBMCs) of patients with SLE through a CRISPR activation approach. Results: We identified shared and cell‐specific enhancers of miR‐146a in distinct immune cells. An enhancer 32.5 kb downstream of miR‐146a possesses less accessibility in SLE, and its chromatin openness was negatively correlated with SLE disease activity. Moreover, CCAAT/enhancer binding protein α, a down‐regulated transcription factor in patients with SLE, binds to the 32.5‐kb enhancer and induces the epigenomic change of this locus. Furthermore, CRISPR‐based activation of this enhancer in SLE PBMCs could inhibit the activity of interferon pathway. Conclusion: Our work defines a promising target for SLE intervention. We adopted integrative approaches to define cell‐specific and functional enhancers of the SLE critical gene and investigated the mechanism underlying its dysregulation mediated by a lupus‐related enhancer. [ABSTRACT FROM AUTHOR]

Objective: Emerging evidence indicates that a distinct CD11c+T‐bet+ B cell subset, termed age/autoimmune‐associated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC‐mediated autoimmunity. Methods: We developed a T‐bet–tdTomato reporter mouse strain to trace live T‐bet+ B cells and adoptively transferred CD4+ T cells from bm12 mice to induce lupus. We next sorted CD11c+tdTomato+ B cells and conducted RNA sequencing and an extracellular flux assay. A metabolic restriction to constrain ABC formation was tested in human and mouse B cells. We used a bm12‐induced lupus mouse model to conduct the metabolic intervention. Results: ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by interferon‐γ (IFNγ) signaling. T‐bet, a downstream transcription factor of IFNγ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody‐secreting cells. Administration of a glycolysis inhibitor ameliorated ABC accumulation and autoantibody production in the lupus‐induced bm12 mouse model. Conclusion: T‐bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulation of ABCs favored a metabolic program that could be a novel therapeutic approach for lupus. [ABSTRACT FROM AUTHOR]

Objective: Type I interferons (IFNs) are critical in the development of systemic lupus erythematosus (SLE). Metabolic abnormalities cause dysregulation of multiple immune cells, but the metabolic regulation of type I IFN production is not well clarified in SLE. We undertook this study to define amino acid metabolism features in SLE and to explore the function of disease‐relevant metabolites in the control of plasmacytoid dendritic cell (pDC)–mediated type I IFN production and the progression of SLE. Methods: Metabolomic profiling of the serum from SLE patients and healthy controls was performed by mass spectrometry. The effects of SLE‐related metabolites on type I IFN production were explored in human and mouse pDCs. The reactive oxygen species (ROS) levels of pDCs from wild‐type and Ncf1−/− mice were measured by flow cytometry. Mechanisms were investigated by RNA sequencing and immunoblotting. In vivo effects of SLE‐relevant metabolites were systemically analyzed in B6.Cg‐Sle1NZM2410/Aeg Yaa/DcrJ mice. Results: Taurine was higher in the serum from SLE patients compared to healthy controls (P < 0.001) and rheumatoid arthritis patients (P < 0.001). Taurine content was positively correlated with disease activity and the expression of IFN signature genes. The addition of taurine facilitated IFN regulatory factor 7 phosphorylation and enhanced type I IFN production by reducing the ROS levels in pDCs in a neutrophil cytosolic factor 1–dependent manner. Taurine supplementation promoted expression of type I IFN–induced genes, activated lymphocytes, and increased autoantibodies and proteinuria, leading to more serious nephritis. Conclusion: Taurine metabolism is involved in the development of SLE by enhancing pDC‐mediated type I IFN production. Targeted inhibition of taurine or implementation of a taurine‐restricted diet has therapeutic potential in SLE. [ABSTRACT FROM AUTHOR]

Objective: Increasing evidence indicates that the cyclic GMP‐AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway has a critical pathogenic role in systemic lupus erythematosus (SLE). Expression levels of the interferon (IFN)–inducible gene IFIT3 are elevated in SLE patients. However, it is still not clear how IFIT3 contributes to the pathogenesis of SLE. This study was undertaken to investigate the activation of the cGAS/STING signaling pathway in human SLE monocytes, and to determine how elevated expression of IFIT3 could contribute to overactive cGAS/STING signaling in patients with SLE. Methods: Monocytes from SLE patients or healthy controls were examined for activity of the cGAS/STING signaling pathway and expression levels of IFIT3. Correlations between cGAS/STING signaling activity and SLE clinical features were analyzed. Gain‐ or loss‐of‐function experiments were used to determine the role of IFIT3 in cGAS/STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT3 and other proteins. Results: The cGAS/STING signaling pathway was found to have enhanced activity in monocytes from SLE patients compared to healthy controls, as indicated by the higher expression of IFNβ downstream. Levels of IFIT3 were significantly elevated in human SLE monocytes, and this was positively correlated with the activity of the cGAS/STING signaling pathway. In vitro, the expression of VACV70‐induced IFNβ was reduced by knockdown of IFIT3, whereas overexpression of IFIT3 produced an opposite effect. Finally, IFIT3 was found to interact with both STING and TANK‐binding kinase 1. Conclusion: These findings suggest that IFIT3 is one of the genes that contributes to the overactive cGAS/STING signaling pathway in human SLE monocytes. IFIT3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS/STING signaling pathway in patients with SLE. [ABSTRACT FROM AUTHOR]

Cyclic GMP-AMP (cGAMP) synthase (cGAS, a.k.a. MB21D1), a cytosolic DNA sensor, catalyzes formation of the second messenger 2’3’-cGAMP that activates the stimulator of interferon genes (STING) signaling. How the cGAS activity is modulated remains largely unknown. Here, we demonstrate that sentrin/SUMO-specific protease 7 (SENP7) interacted with and potentiated cGAS activation. The small ubiquitin-like modifier (SUMO) was conjugated onto the lysine residues 335, 372 and 382 of cGAS, which suppressed its DNA-binding, oligomerization and nucleotidyl-transferase activities. SENP7 reversed this inhibition via catalyzing the cGAS de-SUMOylation. Consistently, silencing of SENP7 markedly impaired the IRF3-responsive gene expression induced by cGAS-STING axis. SENP7-knockdown mice were more susceptible to herpes simplex virus 1 (HSV-1) infection. SENP7 was significantly up-regulated in patients with SLE. Our study highlights the temporal modulation of the cGAS activity via dynamic SUMOylation, uncovering a novel mechanism for fine-tuning the STING signaling in innate immunity. [ABSTRACT FROM AUTHOR]

Objective Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN. Methods Kidney tissues from patients and (NZB × NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFNα-accelerated LN to test its therapeutic efficacy. Results Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFNα-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions. Conclusion MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFNα-accelerated LN, providing potential novel strategies for therapeutic intervention in LN. [ABSTRACT FROM AUTHOR]

Objective Type I interferon (IFN) signaling is regarded as a central pathogenic pathway in systemic lupus erythematosus (SLE). Specific inhibition of this pathway is a core area for the development of new therapies for SLE. This study was undertaken to clarify the pathogenic mechanism involved and to identify new therapeutic targets, using a high-throughput screening platform to determine novel regulators that contribute to the overactivation of the type I IFN signaling pathway in SLE. Methods A high-throughput IFN-stimulated response element (ISRE)-luciferase assay was used to screen for candidate genes that regulate the IFN signaling pathway. Western blotting was used to confirm the regulatory function of CDK1. SYBR Green quantitative reverse transcriptase-polymerase chain reaction was used to detect the expression of individual IFN-stimulated genes (ISGs). The differential expression of CDK1 and ISGs in SLE patients and healthy controls was analyzed using RNA sequencing data and a microarray. Results The high-throughput ISRE-luciferase assay revealed that CDK1 enhanced type I IFN signaling. Consistent with this finding, CDK1 promoted the type I IFN-induced phosphorylation of STAT-1 and the up-regulated expression of ISGs. CDK1 expression was elevated in peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens from SLE patients and correlated positively with their IFN scores. A CDK1 inhibitor reduced the expression of ISGs in PBMCs from SLE patients and in renal cells from mice with lupus. Conclusion Our findings indicate that CDK1 is a positive regulator of the IFN signaling pathway. The overexpression of CDK1 might contribute to the abnormally amplified type I IFN signaling in SLE, and the inhibition of CDK1 could be used to down-regulate type I IFN signaling in SLE. [ABSTRACT FROM AUTHOR]

Objective Systemic lupus erythematosus (SLE) is characterized by the uncontrolled production of inflammatory cytokines, among which type I interferon (IFN) is recognized as a crucial pathogenic factor. The expression of microRNA-146a (miR-146a) is reduced in the white blood cells of SLE patients and accounts for their overactivated inflammatory responses. However, the mechanism of the reduction of miR-146a is still not fully understood. This study was undertaken to test whether the key pathogenic cytokine, type I IFN, is responsible for the dysregulation of miR-146a in SLE. Methods Gene and protein expression was measured in all cells by reverse transcription-quantitative polymerase chain reaction, Northern blotting, or Western blotting. In THP-1 cells, expression of monocyte chemotactic protein-induced protein 1 (MCPIP-1) was knocked down with a lentivirus encoding a short hairpin RNA targeting MCPIP1. The cells were pretreated with type I IFN and assessed for gene expression levels of miR-146a. White blood cells from patients with SLE were analyzed for the expression of the IFN-inducible genes MCPIP1 and miR-146a, and the gene expression data were compared for correlation. Results Pretreatment of THP-1 cells with type I IFN attenuated the induction of miR-146a posttranscriptionally, by down-regulating the expression of pre-miR-146a but not pri-miR-146a or its original unspliced transcript. Expression of MCPIP-1, which was enhanced by type I IFN, was found to be responsible for the inhibition of miR-146a. In white blood cells from patients with SLE, MCPIP1 expression was elevated, and its expression correlated positively with the IFN score and negatively with the miR-146a transcript level. Conclusion Type I IFN inhibits the maturation of miR-146a through the up-regulation of MCPIP-1, and thus contributes to the uncontrolled inflammation and excessive inflammatory gene expression in SLE. [ABSTRACT FROM AUTHOR]

The article focuses on a study of MicroRNA-146a which contributes to abnormal activation of the type I interferon pathway in patients with systematic lupus erythematosus (SLE). SLE is a complex autoimmune disease that is characterized by chronic immune activation and multiple immunologic phenotypes. MicroRNA is identified as regulators that modulate target gene expression, which contributes to the pathogenesis of (SLE). Details on the biologic function of miR-146a are discussed.

The article investigates factors that can possibly impair the suppressive function of CD4+,CD25+ regulatory T cells among patients with untreated active systemic lupus erythematosus (SLE). According to the authors, CD4+,CD25+, FoxP3+ cells were higher in the peripheral blood of patients with SLE compared with normal subjects. They reveal that blockade of Treg cell-mediated suppression by interferon alpha-producing antigen-presenting cells may be a contributing factor to loss of tolerance to SLE.

2′5′-Oligoadenylate synthetase (OAS) was shown to be related to systemic lupus erythematosus (SLE) 20 years ago, and was rediscovered to be involved in type I interferon pathway in SLE by several microarray gene expression studies recently. The goal of this study was to investigate OAS isoform expressions in lupus patients, to evaluate whether they could become biomarkers to differentiate between disease flare and infection. Fifty-four SLE patients presented with fever or systemic inflammatory syndrome, or both, were enrolled. Gene expressions of OAS1, OAS2, and OASL were studied by using real time PCR in active SLE (SLEDAI ≥9, n=29) and in those complicated with infections ( n=25). The latter group was composed of 19 patients with invasive bacterial infections, and six patients with viral infections. C reactive protein (CRP) and other clinical parameters were also measured. Twenty-nine healthy individuals made up a normal control group. The mRNA expressions of OAS1, OAS2, and OASL were higher in patients with lupus flares than those with infections ( p<0.03), or normal controls ( p<0.001). SLE complicated with infections have higher OAS1 expression level ( P=0.002), lower OASL ( P=0.004), and equivalent OAS2 ( P=0.135), when compared with those of normal controls. OASL expression level was negatively correlated with infection in lupus by logistic regression analysis ( p=0.008). Area under the receiver operating characteristic curve for the prediction of infection was 0.92 ( p<0.0001) for OASL, and 0.77 ( p=0.007) for CRP. Therefore, our preliminary data suggest that the pattern of OAS isoform expressions, OASL in particular, may provide useful information in differentiating disease flares from certain infections in SLE. [ABSTRACT FROM AUTHOR]

Renal mesangial cells (RMCs) constitute a population of cells in glomerular mesangium. Inflammatory cytokines produced by RMCs play a vital role in renal inflammation. miRNAs are key regulators of inflammatory cytokine expression. The abnormal expression of renal miRNAs and the consequent changes in inflammatory signal transduction are closely associated with renal inflammation. However, our knowledge of the functions of renal miRNAs is still limited. In this study, we investigated the role of miR-744 in type I interferon (IFN) signaling pathway in primary human RMCs. We show that overexpression of miR-744 enhances IFN-induced CCL2, CCL5, CXCL10, and IL6 expression specifically in RMCs. We found that the activation of TYK2, STAT1 and STAT3 was significantly enhanced by miR-744. miR-744 also enhanced the activation of non-classical signal components, such as ERK and p38. We then identified PTP1B, a ubiquitously expressed phosphatase, as the target of miR-744 that is responsible for enhancing type I IFN response. Finally, miR-744 expression was induced by type I IFN in RMCs. Collectively, our data indicate that by targeting PTP1B, miR-744 plays a feed-forward role in regulating type I IFN signaling pathway. These findings give us new insights into the functions of renal miRNAs in regulating important signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) constitute a heterogeneous population of professional antigen presenting cells which are the initiators and key regulators for both immunity and tolerance induction. The significance and impact of DC biology in contemporary immunology and medical research is heightened by the award of the 2011 Nobel Prize for Medicine and Physiology to Ralf Steinman for his discovery and subsequent work on the role of DC in adaptive immunity. As a central regulator of immune responses, DCs also play a pivotal role in the pathogenesis of chronic inflammatory autoimmune conditions such as systemic lupus erythematosus (SLE). In this review, we will focus on the respective role of the two major subsets of blood DC, namely myeloid (m)-DC and plasmacytoid (p)-DC, in SLE immunopathogenesis. Accumulating evidence has highlighted pDCs as the culprit for SLE pathogenesis, mainly through type-I interferon production. Latest findings in the field also decipher the mechanisms by which pDCs interact with neutrophils and platelets and contribute to SLE development. The recent surge of interest in studying microRNA regulation in SLE pathogenesis will also be discussed. [Copyright &y& Elsevier]

Abstract: Sjögren''s syndrome is a chronic autoimmune disease characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and mouth. Genetic predisposition, pathogenic infections and hormones have been implicated in the pathogenesis of the disease. Studies in the last several years have revealed marked over-expression of the type I interferon (IFN)-inducible genes in the peripheral blood and salivary glands of patients with Sjögren''s syndrome. The expression of the type I IFN-inducible genes in Sjögren''s syndrome also positively correlates to titers of anti-Ro and anti-La autoantibodies, which are typical for this disease. Plasmacytoid dendritic cells (pDC) are the major source of type I IFN production and activated pDC are detected in minor salivary gland biopsies from patients with primary Sjögren''s syndrome. In addition, polymorphisms in genes important both for the production and response to type I IFN are associated to increased risk for Sjögren''s syndrome. Because type I IFN bears a variety of biological functions, such as defense against viral infections and activation of the immune system, these results suggest that the type I IFN system has an important role in the pathogenesis of Sjögren''s syndrome. A variety of mechanisms causing an activation of the type I IFN system are discussed in this review. Given the pivotal role of type I IFN in the disease process, therapeutic interventions targeting the type I IFN signaling pathway have the potential to benefit the patients with elevated type I IFN status and such hypothesis needs to be carefully evaluated in clinical development. [Copyright &y& Elsevier]