Chronic Activation of pDCs in Autoimmunity is linked to Dysregulated ER Stress and Metabolic Responses
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211230 | GEO | 2022/08/15
REPOSITORIES: GEO
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Project description:To identify potential dysregulation of miRNA expression in plasmacytoid dendritic cells from Systemic Sclerosis patients (SSc), miRNA profiling was performed in pDCs from healthy donors or patients with the most severe fibrotic cutaneous form of SSc, namely in dcSSc, with either disease duration shorter (edcSSc) or longer than two years (ldcSSc). Plasmacytoid dendritic cells (pDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to pDC dysregulation and persistent type I IFN signature are largely unexplored, especially in systemic sclerosis (SSc), a disease in which pDCs infiltrate fibrotic skin lesions and produce higher levels of IFNa as compared to healthy controls. To investigate potential microRNA–mediated epigenetic mechanisms underlying pDC dysregulation and type I IFN production in SSc. microRNA expression profiling and validation was performed in highly purified pDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miR-618 on pDC biology were identified by overexpression in healthy pDCs. miR-618 expression was upregulated in pDCs of SSc patients, including those in the early stage of disease onset and not presenting with skin fibrosis. IRF8, a crucial transcription factor for pDC development and activation, was identified as a target of miR-618. miR-618 overexpression reduced the development of pDCs from CD34+ cells in-vitro and enhanced their ability to secrete IFNα, mimicking the pDC phenotype observed in SSc patients. miR-618 upregulation suppresses pDC development and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of pDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.
2020-07-05 | GSE100867 | GEO
Project description:Autoantibodies to nuclear antigens are hallmarks for diagnosis of the autoimmune disease systemic lupus erythematosus (SLE) and they contribute to SLE pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to key disease processes, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). Here, we show that individuals with SLE have IgA autoantibodies against most nuclear antigens assessed, largely correlating with the amounts of IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoproteins (Sm/RNPs), play a role in IC activation of pDCs. We found that pDCs express the IgA-specific Fc receptor, FcRI, and there was a striking ability of IgA1 isotype autoantibodies to synergize with IgG in RNA-containing ICs to generate robust pDC IFN responses. pDC responses to these ICs required both FcRI and FcRIIa, suggesting the most potent ICs for pDCs contained autoantibodies of both isotypes. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. In addition, binding of Sm/RNP ICs generated with IgA1-sufficient serum correlated to pDC FcRI expression, but not FcRIIa expression. pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcRI than pDCs from healthy control individuals, correlating with expression of IFN response genes. Taken together, our data indicate that IgA1 ANAs contribute to SLE pathology and warrant further investigation.
2023-10-19 | GSE242721 | GEO
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE149415 | GEO
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE148902 | GEO
Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.
2020-05-16 | GSE131404 | GEO
Project description:Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods: We evaluated 34 human liver explants. Cohorts included: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results: Metascape pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and could be targeted to treat pediatric CLD.
2022-06-23 | GSE206364 | GEO
Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases. pDCs from healthy donors (n=4) were treated with gardiquimod (TLR7 agonist) or ODN 2216 (TLR9 agonist) with or without BTK inhibitor for 3 hours.
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Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition and tissue inflammation such as glomerulonephritis. Innate recognition of molecular complexes containing self-DNA and RNA and the ensuing production of type I interferons (IFN) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a relevant source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question using haplodeficiency of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that Tcf4+/- animals were significantly protected from SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. The protection was also observed after the monoallelic deletion of Tcf4 specifically in the dendritic cell lineage. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE ameliorated key disease manifestations including anti-DNA antibody production, immune activation and glomerulonephritis. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis, confirming their potential utility as therapeutic targets in the disease. Cellluar suspension were obtained from the spleen of wild type, Sle1.3 and Sle1.3/E2-2het mice. 10 million of cells were used to isolate RNA from each sample. After RNA isolation a microarray analysis using the Ambion WT labeling kit was done. Expression was analyzed using Affymetrix Mouse Gene 1.0 ST. 2 Wild type mice, 3 Sle1.3 and 3 Sle1.3/E2-2 het mice were used for the analysis.
2014-07-30 | E-GEOD-57324 | biostudies-arrayexpress
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition and tissue inflammation such as glomerulonephritis. Innate recognition of molecular complexes containing self-DNA and RNA and the ensuing production of type I interferons (IFN) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a relevant source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question using haplodeficiency of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that Tcf4+/- animals were significantly protected from SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. The protection was also observed after the monoallelic deletion of Tcf4 specifically in the dendritic cell lineage. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE ameliorated key disease manifestations including anti-DNA antibody production, immune activation and glomerulonephritis. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis, confirming their potential utility as therapeutic targets in the disease.
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Project description:Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARγ and C/EBPα. Here we demonstrate that the IRE1α-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1α knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPβ, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1α is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1α-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis.
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