Type I Interferon promotes MxA-dependent IL-1b release in SLE monocytes
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ABSTRACT:
PROVIDER: PRJNA869965 | ENA |
REPOSITORIES: ENA
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Project description:Systemic lupus erythematosus (SLE) is characterized by upregulation of Type Ι Interferon (IFN) and widespread inflammation. However, blocking the IFN pathway benefits a fraction of patients, pointing to additional pathogenic players. Here we describe monocytes (Mo) undergoing erythrophagocytosis and co-expressing IFN-inducible genes (ISGs) and interleukin-1b (IL-1b) in patients with active disease. This phenotype is recapitulated in vitro upon internalization of red blood cells carrying mitochondria (Mito+ RBCs), a feature of SLE. While ISG expression requires the interaction between Mito+ RBC-derived mitochondrial DNA (mtDNA) and cGAS, the production of IL-1b entails Mito+ RBC-derived mitochondrial RNA (mtRNA) triggering RIG-I-like receptor (RLR) activation. This leads to the cytosolic release of Mo-derived mtDNA and activation of the NLRP3 inflammasome. Importantly, the Type I IFN-inducible protein myxovirus resistant protein 1 (MxA) enables IL-1b release by routing this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. As Type I IFN and IL-1b are thought to counter-regulate each other, our study highlights an unprecedented synergy between these two cytokine pathways in SLE.
2024-10-07 | GSE211361 | GEO
Project description:To better characterize the molecules that could potentially confer antigen presenting capacity to SLE monocytes, we assessed their gene expression profile. Blood monocytes from five healthy controls and five pediatric SLE patients were isolated using CD14+ selection. Because drugs used to treat SLE could induce considerable transcriptional changes, we selected active, newly diagnosed patients who had never received oral or intravenous (IV) medications.
2014-06-03 | E-GEOD-46907 | biostudies-arrayexpress
Project description:Mature neutrophis were freshly isolated from blood of pediatric systemic lupus erythematosus (SLE) patients and healthy donors. Illumina microarray was used to assess transcriptional changes between SLE group and Control group. To uderstand further the gene expression difference between SLE and healthy neutrofils, neutrophils from healthy donors were cultured with autologous sera, SLE sera or Interferon and microarray data was used to compare with fresh SLE neutrophils. (Expt 1) Neutrophils from 21 SLE samples (19 patients) and 12 healthy donors were isolated, and extracted RNAs were used generate microarray data. (Expt 2) Neutrophils isolated from 2 healthy children (not used in the first experiment) were cultured with autologous sera (control), Interferon alpha (100U and 1000U), and 4 SLE sera and 6 SLE sera for 6 hours and RNAs were extract for microarray experiment.
2011-03-10 | E-GEOD-27427 | biostudies-arrayexpress
Project description:Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as TNFα in RA and IFNα/γ in SLE. To relate the transcriptional imprinting of cytokines in a cell type-specific and disease-specific manner, we generated gene-expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNFα, IFNα2a and IFNγ. Monocytes from SLE and RA patients revealed disease-specific gene-expression profiles. In vitro-generated signatures induced by IFNα2a and IFNγ showed similar profiles that only partially overlapped with those induced by TNFα. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN-responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNFα-regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNFα that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene-expression profiles, which can be molecularly dissected when compared to in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention. Expression profiles of human peripheral blood monocytes activated in vivo and stimulated in vitro. Monocytes from patients with SLE and RA and from healthy donors were used for generating disease-specific gene-expression profiles, where these profiles represent in vivo activation of monocytes. In addition, monocytes from healthy donors were stimulated in vitro by cytokines: TNFα, IFNα2a and IFNγ. Cytokine-specific gene-expression profiles were generated by comparing stimulated monocytes with unstimulated ones. TNFα-, IFNα2a- and IFNγ as cytokine-specific gene-expression profiles were compared with RA and SLE, as disease-specific gene-expression profiles.
2012-06-13 | E-GEOD-38351 | biostudies-arrayexpress
Project description:To better characterize the molecules that could potentially confer antigen presenting capacity to SLE monocytes, we assessed their gene expression profile.
2014-06-03 | GSE46907 | GEO
Project description:Monocytes from 3 healthy donors were cultured for 6 hours in the presence of 20% serum from three newly diagnosed, untreated SLE patients. Microarray analysis was then performed upon normalizing the gene expression levels of samples incubated with SLE sera to those incubated with autologous serum. Monocytes from 3 healthy donors were cultured for 6 hours in the presence of 20% serum from three newly diagnosed, untreated SLE patients. Microarray analysis was then performed upon normalizing the gene expression levels of samples incubated with SLE sera to those incubated with autologous serum.
2014-06-03 | E-GEOD-46920 | biostudies-arrayexpress
Project description:We screened SLE monocytes from 19 SLE patients and selected 4 that induced CD4+ T cell proliferation in vitro and 4 that did not. CFSE labeled CD4-T cells (105) were incubated with SLE monocytes (2 x 104). Cells were harvested at 6 hours for RNA extraction. We screened SLE monocytes from 19 SLE patients and selected 4 that induced CD4+ T cell proliferation in vitro and 4 that did not. CFSE labeled CD4-T cells (105) were incubated with SLE monocytes (2 x 104). Cells were harvested at 6 hours for RNA extraction.
2014-06-03 | E-GEOD-46917 | biostudies-arrayexpress
Project description:Mature neutrophis were freshly isolated from blood of pediatric systemic lupus erythematosus (SLE) patients and healthy donors. Illumina microarray was used to assess transcriptional changes between SLE group and Control group. To uderstand further the gene expression difference between SLE and healthy neutrofils, neutrophils from healthy donors were cultured with autologous sera, SLE sera or Interferon and microarray data was used to compare with fresh SLE neutrophils.
2011-03-10 | GSE27427 | GEO
Project description:Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as TNFα in RA and IFNα/γ in SLE. To relate the transcriptional imprinting of cytokines in a cell type-specific and disease-specific manner, we generated gene-expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNFα, IFNα2a and IFNγ. Monocytes from SLE and RA patients revealed disease-specific gene-expression profiles. In vitro-generated signatures induced by IFNα2a and IFNγ showed similar profiles that only partially overlapped with those induced by TNFα. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN-responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNFα-regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNFα that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene-expression profiles, which can be molecularly dissected when compared to in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention.
2012-06-14 | GSE38351 | GEO
Project description:Current non-specific immunosuppressive treatments for Systemic Lupus Erythematosus (SLE) show modest efficacy. In SLE the monocytic/macrophage (Mo/Mφ) system plays a key role in the initiation and perpetuation of the systemic autoimmune response. However, the distinct functions of the Mo/Mφ cellular subsets remain elusive. Herein, we demonstrate a distinct proteomic and transcriptomic profile of non-classical monocytes (NCM) of active patients with SLE with enhanced inflammatory features such as deregulated DNA repair, cell cycle and enhanced IFN signaling in parallel with cell differentiation and developmental cues. Ex-vivo assays revealed an upregulation of p53 due to enhanced DNA damage along with G0 cell cycle arrest of SLE NCM indicative of an inflammatory phenotype. This aberrant profile of NCM of active patients with SLE is linked with an activated macrophage-like and enriched M1 pro-inflammatory response. We envisage that enhanced autophagy in SLE NCM may drive their differentiation towards an M1-like macrophage profile contributing to disease severity. Together, these findings provide evidence of skewed differentiation of NCM towards an M1-like macrophage phenotype as a pathogenic feature of NCM in SLE.
2023-11-21 | PXD042539 | Pride