| 1. |
- Chandrasekaran, Venkatagaran, et al.
(författare)
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Cohesin-Mediated Chromatin Interactions and Autoimmunity
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFN gamma signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.
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| 2. |
- Erlandsson, Malin, 1972, et al.
(författare)
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IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses.The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing.Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs.In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.
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| 3. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing Tcells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4+T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4+ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4+ cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4+ cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4+T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.
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| 4. |
- Jensen, Maja, 1978, et al.
(författare)
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Survivin prevents the polycomb repressor complex 2 from methylating histone 3 lysine 27
- 2023
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Ingår i: Iscience. ; 26:7
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Tidskriftsartikel (refereegranskat)abstract
- This study investigates the role of survivin in epigenetic control of gene transcription through interaction with the polycomb repressive complex 2 (PRC2). PRC2 is responsible for silencing gene expression by trimethylating lysine 27 on histone 3. We observed differential expression of PRC2 subunits in CD4(+) T cells with varying levels of survivin expression, and ChIP-seq results indicated that survivin colocalizes with PRC2 along DNA. Inhibition of survivin resulted in a significant increase in H3K27 trimethylation, implying that survivin prevents PRC2 from functioning. Peptide microarray showed that survivin interacts with peptides from PRC2 subunits, and machine learning revealed that amino acid composition contains relevant information for predicting survivin interaction. NMR and BLI experiments supported the interaction of survivin with PRC2 subunit EZH2. Finally, protein-protein docking revealed that the survivin-EZH2 interaction interface overlaps with catalytic residues of EZH2, potentially inhibiting its H3K27 methylation activity. These findings suggest that survivin inhibits PRC2 function.
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| 5. |
- Larsson, Carolina, et al.
(författare)
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MicroRNA and interleukin 6 interplay in the adipose tissue of rheumatoid arthritis patients.
- 2023
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Ingår i: Clinical and experimental rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 41:1, s. 32-40
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRs) are non-translated RNA sequences that elicit negative control over protein expression. The adipose tissue (AT) is considered the major producer of miRs and inflammatory interleukin 6 (IL-6). This study aims to investigate the relationship between production of IL-6 and miRs in AT.IL-6 gene expression was analysed in RNA extracts from subcutaneous AT of 75 patients with rheumatoid arthritis (RA), with qPCR. Genome-wide profile of human miRs (2565 miRs, 96.6%) was analysed in 35 AT samples on 3D microarray. The miR-processing proteins Dicer, Drosha and DGCR8 were analysed with qPCR. In silico prediction of protein targets for the differentially expressed (DE) miRs (p<0.05; log2FC >±0.5) was conducted by DIANA software. Seven AT samples were stimulated in vitro with IL-6 or IL-6+IL-6R antibody tocilizumab and analysed for the miR processing proteins.We identified 30 DE miRs between AT with high and low IL-6 mRNA, of which 26 miRs were inversely related with IL-6 levels. DE miRs were predicted to interfere in oestrogen (p=0.001), FoxO (p=0.006) and insulin (p=0.03) signalling pathways. High expression of IL-6 in AT was associated with significantly higher expression of Dicer (p=0.04) and Drosha (p=0.04), while inhibition of IL-6 signalling with tocilizumab decreased the levels of total miRs processing enzymes (p=0.003).IL-6 mRNA production in AT has a negative effect on the miRs expression profile and it increases miR-production capacity.
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| 6. |
- Lyngfelt, Lovisa, et al.
(författare)
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Impact of the Uncoupling Protein 1 on Cardiovascular Risk in Patients with Rheumatoid Arthritis
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Adiposity is strongly associated with cardiovascular (CV) morbidity. Uncoupling protein 1 (UCP1) increases energy expenditure in adipocytes and may counteract adiposity. Our objective was to investigate a connection between UCP1 expression and cardiovascular health in patients with rheumatoid arthritis (RA) in a longitudinal observational study. Transcription of UCP1 was measured by qPCR in the subcutaneous adipose tissue of 125 female RA patients and analyzed with respect to clinical parameters and the estimated CV risk. Development of new CV events and diabetes mellitus was followed for five years. Transcription of UCP1 was identified in 89 (71%) patients. UCP1 positive patients had often active RA disease (p = 0.017), high serum levels of IL6 (p = 0.0025) and were frequently overweight (p = 0.015). IL-6(hi)BMI(hi) patients and patients treated with IL6 receptor inhibitor tocilizumab had significantly higher levels of UCP1 compared to other RA patients (p < 0.0001, p = 0.032, respectively). Both UCP1(hi) groups displayed unfavorable metabolic profiles with high plasma glucose levels and high triglyceride-to-HDL ratios, which indicated insulin resistance. Prospective follow-up revealed no significant difference in the incidence of new CV and metabolic events in the UCP1(hi) groups and remaining RA patients. The study shows that high transcription of UCP1 in adipose tissue is related to IL6-driven processes and reflects primarily metabolic CV risk in female RA patients.
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| 7. |
- Malmhäll-Bah, Eric, et al.
(författare)
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Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14+ cells in rheumatoid arthritis.
- 2023
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Ingår i: Frontiers in immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects.CD14+ cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CDC42 hiCD14+ cells, which were summarized in a metabolic signature (MetSig). The effect of hypoxia and IFN-γ signaling on the metabolic signature of CD14+ cells was assessed experimentally. To investigate its connection with joint inflammation, the signature was translated into the single-cell characteristics of CDC42 hi synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically.CDC42 hiCD14+ cells carried MetSig of genes functional in the oxidative phosphorylation and proteasome-dependent cell remodeling, which correlated with the cytokine-rich migratory phenotype and antigen-presenting capacity of these cells. Integration of CDC42 hiCD14+ and synovial macrophages marked with MetSig revealed the important role of the interferon-rich environment and immunoproteasome expression in the homeostasis of these pathogenic macrophages. The CDC42 hiCD14+ cells were targeted by JAK inhibitors and responded with the downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production, and alleviated arthritis.This study shows that the CDC42-related MetSig identifies the antigen-presenting CD14+ cells that migrate to joints to coordinate autoimmunity. The accumulation of CDC42 hiCD14+ cells discloses patients perceptive to the JAKi treatment.
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| 8. |
- Malmhäll-Bah, Eric, et al.
(författare)
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Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis
- 2022
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4(+) T cells from GLC mice (CD4(+)GLCs). Spleen and joint draining lymph nodes (dLN) CD4(+)GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4(+)GLCs presented a complete signature of GARP(+)NRP1(+)IKZF2(+)FOXP3(+) regulatory T cells (Tregs) of thymic origin. Activation of the beta-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4(+) cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4(+) cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4(+)GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthri-togenic phenotype.
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| 9. |
- Nadali, Mitra, et al.
(författare)
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Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients. Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed. Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years. Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD.
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| 10. |
- Wasén, Caroline, et al.
(författare)
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Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8(+)T Cells in Rheumatoid Arthritis
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8(+)T cell memory formation through a microRNA (miR) dependent mechanism. Methods:Phenotypes of CD8(+)T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8(+)cells werein vitrostimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR. Results:CD27(+)CD107a(-)CD8(+)T cells, defining a naive-memory population, had low expression of PD-1. Additionally, the CD27(+)population was more frequent in smokers (p= 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8(+)memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8(+)cells with naive-memory predominance. Nicotine exposure of CD8(+)cells induced the expression of miR-150-5p and miR-181a-5p in the naive-memory cellsin vitro. Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs. Conclusions:Smokers have a high prevalence of CD8(+)T cells with a naive-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.
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