Role In Systemic Lupus Erythematosus Research Articles

Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus.

Low-density lipoprotein (LDL) levels are increased by proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL receptor. We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and is also associated with cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Here, we investigated the role of PCSK9 in SLE. PCSK9 levels were determined by ELISA among SLE patients (N = 109) and age- and sex-matched population-based controls (N = 91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. The effects of PCSK9 and its inhibition by silencing were studied. PCSK9 levels were non-significantly higher among SLE-patients compared to controls but significantly associated with SLE disease activity, as determined by the Systemic Lupus Activity Measure (p = 0.020) or the SLE Disease Activity Index (p = 0.0178). There was no association between PCSK9 levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE patients but not after adjusting for age. OxLDL induced PCSK9 in DCs and DC maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DCs from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC maturation. PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL promoting DC activation which depends on PCSK9. OxLDL induces PCSK9 - an effect which is higher among SLE patients. PCSK9 could play an unexpected immunological role in SLE.

Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus.

Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.

Evaluation of Peripheral Blood Leukocyte Subsets in Systemic Lupus Erythematosus (SLE) Enabled by a Microfluidic Cell Separator

Abstract Although granulocyte signatures have been associated with SLE severity, their role in SLE has been poorly understood due to the suboptimal methods for granulocyte recovery from peripheral blood. An automated microfluidic technology (Sorterra™ prototype) was used to isolate all leukocytes with minimal platelet (PLT) or red blood cell (RBC) contamination to assess the cell subsets. Leukocytes were isolated from peripheral blood collected from healthy donors (HD) and SLE patients (3 female, 3 male in each group) using Sorterra, RBC lysis, or Ficoll®. Viability and recovery of each leukocyte subset was evaluated by cell counter and flow cytometry. Sorterra recovered 92±4% of leukocytes from HD and SLE samples with negligible RBC/PLT/microparticle (MP) contamination, whereas Ficoll isolated 35±15% of leukocytes, losing nearly all the granulocytes and retaining a substantial level of RBC/PLT/MP. With RBC lysis, up to 65% of neutrophils and 41% of eosinophils were lost in the process. Sorterra recovered more monocytes (~80%) than Ficoll (p<0.05). The recovery of lymphocytes by Sorterra (~90%) was not different from Ficoll or RBC lysis. The recovery of T and B cell subsets, NK, and NKT cells, was also not different among the isolation methods. The viability of Sorterra isolated leukocytes was significantly higher than the Ficoll isolated cells. The Sorterra prototype was superior to RBC lysis and Ficoll in recovering total leukocytes with high viability and ease of use and provided a more consistent leukocyte isolate from HD and SLE patients than other methods. The ability to recover granulocytes in their native state is unmatched by existing technologies and enables future studies to better elucidate the role of granulocytes in SLE development.

Anti-CD19 CAR-T cell therapy for Systemic Lupus Erythematosus in a mouse disease model

Abstract Dysregulated B cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell-depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 chimeric antigen receptor (CAR) T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy into SLE treatment in a mouse disease model. We have constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic functions of corresponding CAR-T cells by infusing them into MRL-lpr mice. We found that adoptive transfer of anti-CD19 CAR-T cells was able to achieve sustained B-cell-depletion in MRL-lpr mice. More importantly, transferring syngeneic anti-CD19 CAR-T cells can not only prevent disease pathogenesis before the onset of disease symptoms but also have substantial therapeutic benefits in disease treatment at a later stage after disease progression. Comparing to CAR-T cells with CD28 as a costimulatory motif, CAR-T cells with 4-1BB costimulatory motif work better for mouse SLE treatment. In summary, our study claimed that anti-CD19 CAR-T cell therapy worked effectively in treating murine SLE, indicating its potential in treating human patients in clinic.

Double Negative B Cell Is Associated With Renal Impairment in Systemic Lupus Erythematosus and Acts as a Marker for Nephritis Remission.

Objective: Recent studies on double negative B cells (DN B cells) suggested that they have potential pathogenic roles in systemic lupus erythematosus (SLE). This study aimed to determine the circulating DN B cells in SLE patients and analyzed the clinical significance of this cell subset.Methods: Fifty-seven SLE patients and fifty healthy controls (HCs) were recruited in this study. Among the 57 SLE patients, 25 had lupus nephritis (LN). All patients were followed up for 24 weeks. Peripheral B cell subsets were analyzed by flow cytometry.Results: DN B cells were significantly elevated in the SLE patients, especially in the patients with LN (p < 0.01). DN B showed a positive correlation with 24-h urine protein excretion (24 h-UPE) levels (r = 0.444, p = 0.034) in LN patients, and inversely correlated with evaluated glomerular filtration rate (eGFR) (r = −0.351, p = 0.011). DN B cells had a positive correlation with plasma cells (r = 0.484, p < 0.001) and memory B cells (r = 0.703, p < 0.001). After treatment, decreased DN B cells were associated with LN alleviation (p = 0.002). In the follow-up, the remission rate of LN patients with decreased DN B cells was significantly higher than LN patients with increased DN B cells (83.33 vs. 25.00%, p = 0.030) at week 24.Conclusions: This study suggests that the peripheral DN B cells are positively correlated with the severity of renal damage in LN patients and may potentially be used as a prognostic marker in LN.

Serum levels of soluble programmed cell death protein 1 and soluble programmed cell death protein ligand 2 are increased in systemic lupus erythematosus and associated with the disease activity.

Programmed cell death protein 1 (PD-1) pathway plays important roles in systemic lupus erythematosus (SLE). We aimed to elucidate the association of serum soluble PD-1 (sPD-1) and related molecules with SLE and to explore their usefulness as biomarkers. We retrospectively measured the serum levels of sPD-1, soluble PD-ligand 1 (sPD-L1), soluble PD-ligand 2 (sPD-L2) and interleukin (IL)-21 by ELISA in SLE patients, systemic sclerosis patients and healthy controls. Repeat sera samples were also obtained post treatment. The serum levels of sPD-1 and sPD-L2 in SLE patients with high disease activity were significantly higher than those in SLE patients with low disease activity, systemic sclerosis patients and healthy controls (n = 58, 15, 20 and 21, respectively; p < 0.001). However, the serum levels of sPD-L1 and IL-21 were not elevated in SLE patients. The serum levels of sPD-1 and sPD-L2 were higher among active SLE patients who tested positive for anti-dsDNA antibodies than in those who tested negative (p = 0.002 and <0.001, respectively). There were moderate correlations between the serum levels of sPD-1 and sPD-L2 and the SLE Disease Activity Index 2000 scores, the titres of anti-dsDNA antibodies and the serum levels of complements. Furthermore, the serum levels of sPD-1 and sPD-L2 decreased significantly in accordance with disease amelioration following treatment (p < 0.001). The present study demonstrated the association of serum sPD-1 and sPD-L2 with SLE and suggests their usefulness as disease activity biomarkers for SLE.

Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice.

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

Identification of novel biomarkers in ischemic stroke: a genome-wide integrated analysis

BackgroundIschemic Stroke (IS) is the most common neurological emergency disease and has become the second most frequent cause of death after coronary artery disease in 2015. Owing to its high fatality rate and narrow therapeutic time window, early identification and prevention of potential stroke is becoming increasingly important.MethodsWe used meta-analysis and bioinformatics mining to explore disease-related pathways and regulatory networks after combining messengerRNA (mRNA) and miRNA expression analyses. The purpose of our study was to screen for candidate target genes and microRNA(miRNA) for early diagnosis of potential stroke.ResultsFive datasets were collected from the Gene Expression Omnibus (GEO) database by systematical retrieval, which contained three mRNA datasets (102 peripheral blood samples in total) and two miRNA dataset (59 peripheral blood samples). Approximately 221 different expression(DE) mRNAs (155 upregulated and 66 downregulated mRNAs) and 185 DE miRNAs were obtained using the metaDE package and GEO2R tools. Further functional enrichments of DE-mRNA, DE-miRNA and protein-protein interaction (PPI) were performed and visualized using Cytoscape.ConclusionOur study identified six core mRNAs and two regulated miRNAs in the pathogenesis of stroke, and we elaborated the intrinsic role of systemic lupus erythematosus (SLE) and atypical infections in stroke, which may aid in the development of precision medicine for treating ischemic stroke. However, the role of these novel biomarkers and the underlying molecular mechanisms in IS require further fundamental experiments and further clinical evidence.

Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6+B helper T cells in systemic lupus erythematosus

Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells were phenotypically distinct from follicular helper T (TFH) cells and lacked BCL6 expression. In peripheral blood, a CCR6+T cell population with similar characteristics was identified, which lacked Th17- and TFH-associated gene signatures and differentiation-associated surface markers. CD4+CCR6+T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4+CCR6+IL-7R+T cells were associated with the presence of pathogenic anti-dsDNA (double-stranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10-producing CCR6+T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.

Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network in systemic lupus erythematosus.

A new perspective of determining the pathophysiology of systemic lupus erythematosus (SLE) development is required. The current study explores the aberrant expression of long non-coding RNAs (lncRNA), microRNA (miRNA) and mRNA. The study further constructs and analyses the lncRNA-miRNA-mRNA network to elucidate their gene regulation roles in SLE. We extracted mRNA, lncRNA and miRNA from the whole venous blood of 20 SLE patients and 20 normal control (NC) healthy individuals. A lncRNA-mRNA-miRNA network in SLE was constructed using a bioinformatics approach. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the Cytoscape plug-in BinGo, the DAVID database and Cytoscape software to explore the function of mRNAs in this network. A total of 855 mRNA, 7311 lncRNA and 134 miRNA with differentially expressed profiles were identified. Meanwhile, we established a competing endogenous RNA (ceRNA) subnetwork composed of 52 differentially expressed lncRNAs (DElncRNAs), seven differentially expressed miRNAs and 10 differentially expressed mRNAs. We extracted the subnetwork from the ceRNA network and found that three novel miRNAs were key: hsa-miR-145, hsa-miR-17 and hsa-miR-143. We also deduced that the DElncRNAs MIAT and NEAT1 might play crucial roles in the pathogenesis of SLE. The results were verified by bioinformatics analysis. Our results provide a novel perspective for studying lncRNA-related and miRNA-related ceRNA networks in SLE.

The preliminary association study of osteopontin 707 C/T polymorphism with systemic lupus erythematosus in a Polish population.

IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease caused by genetic, environmental, and still unknown factors which lead to deregulation of the immune system. Osteopontin (OPN) is a multifunctional glycoprotein, expressed in various cell types, and found to play key roles in immunity. OPN and variants of the OPN gene are involved in inflammatory conditions, however, their role in SLE are controversial.AimTo investigate the frequency of single nucleotide polymorphism (SNP) rs1126616 (707 C/T) variants in the OPN gene and its associations with SLE manifestations in Polish patients.Material and methodsThe study population consisted of 83 SLE patients and 100 gender-, age- and ethnically matched healthy controls. DNA was extracted from whole blood samples using the standard procedure. Genotyping was performed by real-time polymerase chain reaction (RT-PCR). The association between clinical features of SLE and 707 C/T genotypes was determined.ResultsThe mutant (CT, TT) genotypes were observed more frequently than the wild-type (CC) genotype in SLE patients compared to controls (p = 0.037). However, no association between 707 C/T variants and SLE clinical manifestations or laboratory parameters was found.ConclusionsThe present data suggest that CT and TT genotypes of OPN 707 C/T SNP are associated with a higher SLE risk, but do not affect the clinical course of the disease in the Polish population.

Genome Variation and Precision Medicine in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease which is facing the difficulties in treatment. Genetics play an important role in SLE. Several studies have shown that genetic factors not only affect the development of SLE, but also affect its clinical progress. In this review article, we focus on exploring the influence of genetics on different aspects of SLE pathogenesis, clinical course, and treatment and will provide some references in further precision medicine for SLE patients. The coming era of precision medicine, SLE patients will be stratified by genetic profiling. This will enable us to make more effective and precise choices of treatment plan.

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 associated with an aberrant activation of immune cells partly due to the dysfunction of cytokines such as type I interferons (IFNs). Long non-coding RNA MALAT1 has been found to play a pathogenic role in SLE; however, the underlying mechanisms are still poorly understood. Bioinformatics analysis showed the up-regulation of type I IFN downstream effectors OAS2, OAS3, and OASL (OAS-like) in CD4+ T cells, CD19+ B cells, and CD33+ myeloid cells in patients with active SLE compared to healthy participants. In this study, peripheral blood mononuclear cells (PBMCs), CD19+ B, and CD4+ T cells were isolated from active SLE patients and healthy participants. PCR was performed to quantify MALAT1, OAS2, OAS3, and OASL expression in immune cells. MALAT1, OAS2, OAS3, and OASL were knocked down in CD4+ T cells to investigate the regulatory effect of MALAT1 on the effectors and their involvement in type I IFNs-mediated inflammation. Results showed higher OAS2, OAS3, and OASL expression in active SLE patients. MALAT1 expression was positively correlated to OAS2, OAS3, and OASL expression in CD19+ B or CD4+ T cells. MALAT1 knockdown decreased OAS2, OAS3, and OASL expression. Treatment with IFN-α-2a increased the expression of TNF-α, IL-1β, and IFN-α in CD4+ T cells. However, knockdown of MALAT1, OAS2, OAS3, and OASL alone inhibited the effect of IFN-α-2a on TNF-α and IL-1β. This study suggested the involvement of MALAT1 in type I IFNs-mediated SLE by up-regulating OAS2, OAS3, and OASL.

Interleukin-17 and lupus: enough to be a target? For which patients?

The involvement of the interleukin (IL)-17 axis in many inflammatory and autoimmune diseases is now well established, and this has led to the development of successful targeted therapies. Its role in systemic lupus erythematosus (SLE) is less described, since SLE is characterized by the impairment of many other immune actors. However, results from animal models and patients strongly suggest that IL-17 and its producing cells are involved in SLE pathogenesis. Circulating levels of IL-17 are increased in lupus, and tissue staining shows the presence of IL-17-producing cells in organ lesions. Through different mechanisms, the IL-17 axis promotes autoantibody production, immune complex deposition, complement activation and then tissue damage. There are also many interactions with other immune and non-immune actors, which account for the broad spectrum of clinical manifestations and disease heterogeneity. SLE treatment faces challenges with many disappointing trials and persistent unmet needs. The identification of subsets of SLE patients with an IL-17-driven disease now constitutes the key priority before starting trials. More preclinical studies are needed to improve the selection of the right patients able to respond and tolerate the many inhibitors that are already available.

Stimulation of Mononuclear Cells Through Toll-Like Receptor 9 Induces Release of Microvesicles Expressing Double-Stranded DNA and Galectin 3-Binding Protein in an Interferon-α-Dependent Manner.

Background: Microvesicles (MVs) expressing the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP) may play a pathogenic role in systemic lupus erythematosus (SLE). Co-expression of double-stranded DNA (dsDNA) on such MVs may render them immunogenic and targets for anti-dsDNA antibodies. Little is known about the mechanisms underlying generation of this MV population. In this study, we investigated how Toll-like receptors (TLRs), IFN-α, and T cells are involved in this process in healthy subjects.Methods: Peripheral blood mononuclear cells (PBMCs) isolated from 12 healthy donors were stimulated in-vitro for 24 h with a series of TLR-agonists or the T cell activating antibody OKT3 or were subjected to apoptosis by incubation with staurosporine. MVs in the supernatants were subsequently isolated by differential centrifugation and were quantified and characterized with respect to expression of G3BP and dsDNA by flow cytometry.Results: Stimulation of PBMCs with the TLR9-agonist and strong IFN-α inducer ODN2395 significantly increased the release of MVs expressing G3BP. The production of MVs with this phenotype was markedly enhanced by co-stimulation of T cells. Furthermore, dependency on IFN-α in the generation of G3BP-expressing MVs was indicated by a marked reduction following addition of the IFN-α inhibitor IFN alpha-IFNAR-IN-1 hydrochloride.Conclusion: Release of G3BP-expressing MVs from healthy donor PBMCs is induced by stimulation of TLR9 in an IFN-α-dependent manner and is enhanced by co-stimulation of T cells.

The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus

The AIRE gene influences the expression of a wide array of self-antigens in the thymus, and is essential to the negative selection of self-reactive T cells and establishment of central tolerance. Single nucleotide variants (SNVs) such as rs878081C/T (Ser196Ser) and rs2075876G/T at this locus have been associated with susceptibility to rheumatoid arthritis, mainly in Asian populations, but its role in systemic lupus erythematosus (SLE) has not been documented. We performed a case-control association study with 379 SLE patients and 460 controls from central Mexico. In addition, we replicated our finding in another group of 179 SLE patients and 97 controls from the same region of Mexico. In the first group, we identified that the AIRE Ser196Ser synonymous variant was associated with SLE (OR 1.4, p = 0.009), meanwhile, in the second group we observed the following: OR 1.7, p = 0.024. No association was found between these AIRE SNVs and lupus nephritis. Our results suggest that AIRE is a risk factor for SLE in our population. This study is the first to document an association between AIRE and SLE susceptibility.

Increased HERV-E clone 4\u20131 expression contributes to DNA hypomethylation and IL-17 release from CD4+ T cells via miR-302d/MBD2 in systemic lupus erythematosus

BackgroundIncreased human endogenous retroviruses E clone 4–1 (HERV-E clone 4–1) mRNA expression is observed in systemic lupus erythematosus (SLE) patients and associates with the disease activity. In this study, we want to further investigate the mechanism of HERV-E clone 4–1 mRNA upregulation and its roles in SLE progression.MethodsCD4+ T cells were isolated from venous blood of SLE patients or healthy controls and qRT-PCR was used to detect HERV-E clone 4–1 mRNA expression. We then investigated the regulation of Nuclear factor of activated T cells 1 (NFAT1) and Estrogen receptor-α (ER-α) on HERV-E clone 4–1 transcription and the functions of HERV-E clone 4–1 3′ long terminal repeat (LTR) on DNA hypomethylation and IL-17 release.ResultsWe found HERV-E clone 4–1 mRNA expression was upregulated in CD4+ T cells from SLE patients and positively correlated with SLE disease activity. This is associated with the activation of Ca2+/calcineurin (CaN)/NFAT1 and E2/ER-α signaling pathway and DNA hypomethylation of HERV-E clone 4–1 5’LTR. HERV-E clone 4–1 also takes part in disease pathogenesis of SLE through miR-302d/Methyl-CpG binding domain protein 2 (MBD2)/DNA hypomethylation and IL-17 signaling via its 3’LTR.ConclusionsHERV-E clone 4–1 mRNA upregulation is due to the abnormal inflammation/immune/methylation status of SLE and it could act as a potential biomarker for diagnosis of SLE. HERV-E clone 4–1 also takes part in disease pathogenesis of SLE via its 3’LTR and the signaling pathways it involved in may be potential therapeutic targets of SLE.

Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus

ObjectivesThe presence of proinflammatory low-density granulocytes (LDG) has been demonstrated in autoimmune and infectious diseases. Recently, regulatory neutrophilic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) were identified in systemic lupus erythematosus (SLE)....

Interleukin-25 is upregulated in patients with systemic lupus erythematosus and ameliorates murine lupus by inhibiting inflammatory cytokine production

Interleukin-25 (IL-25), an anti-inflammatory member of the IL-17 family of cytokines, has been extensively investigated in multiple autoimmune and inflammatory diseases. However, its pathogenic role in systemic lupus erythematosus (SLE) remains largely unknown. This study aimed to explore the expression and clinical significance of IL-25 in patients with SLE as well as its pathogenic role in lupus-prone MRL/lpr mice. The results showed that IL-25 mRNA and serum levels were increased in patients with SLE compared with those in healthy controls. Higher IL-25 mRNA and serum levels were found in patients with an active disease. IL-25 levels were positively associated with SLEDAI, anti-dsDNA, and IgG but negatively associated with C3 and C4. Ex vivo assay showed that IL-25 could inhibit the production of the inflammatory cytokines IL-1β, IL-17, IL-6, and IFN-γ as well as TNF-α in the peripheral blood mononuclear cells in patients with SLE. In vivo studies revealed that treatment with IL-25 significantly ameliorated lupus symptoms in lupus-prone MRL/lpr mice by suppressing the production of inflammatory cytokines, including IL-1α, IL-1β, IL-6, IL-12p70, IL-17A, and IFN-β. Cumulatively, our results suggest that IL-25 levels are increased in patients with SLE and associated with disease activity; IL-25 plays a potent immunosuppressive role in the pathogenesis of SLE by suppressing the production of inflammatory cytokines. IL-25 could potentially be used as a diagnostic and therapeutic target for SLE treatment.

Alterations of the Gut Microbiota Associated With Promoting Efficacy of Prednisone by Bromofuranone in MRL/lpr Mice.

Gut microbiota played an important role in systemic lupus erythematosus (SLE) and glucocorticoids were prone to cause alterations in gut microbiota. This study addressed the effect of bromofuranone on the treatment of SLE with prednisone, since bromofuranone could regulate gut microbiota by inhibiting the AI-2/LuxS quorum-sensing. Remarkably, bromofuranone did not alleviate lupus but promoted the efficacy of prednisone in the treatment of lupus. The alterations in the gut microbiota, including decreased Mucispirillum, Oscillospira, Bilophila and Rikenella, and increased Anaerostipes, were associated with prednisone treatment for SLE. In addition, the increase of Lactobacillus, Allobaculum, Sutterella, and Adlercreutzia was positively associated with the bromofuranone-mediated promotion for the treatment of lupus. This was the first study demonstrating that the efficacy of glucocorticoids could be affected by the interventions in gut microbiota.