Biology subjects

Erlandsson, M. C.

Publications and source records attributed to Erlandsson, M. C..

5 recordsLinked to original sources

bioRxiv2025

CD5L insufficiency exacerbates skeletal joint damage in rheumatoid arthritis

CD5L is an immunoregulatory protein induced during inflammation and makes a life-saving contribution in infection and sepsis. Here, we explored the overall impact of CD5L in rheumatoid arthritis (RA). Using experimental RA models, we demonstrated an early surge of CD5L expression in wild-type mice, as well as a higher incidence and increased severity of arthritis in CD5L-deficient mice. In the blood, CD5L-deficient mice exhibited enhanced inflammation, a higher proportion of CD11b mononuclear cells, and elevated levels of IL-1{beta}, IL-17, and IFN-{psi}, particularly at the pre-clinical stage of arthritis. In human RA, mononuclear cells conditioned with CD5L, as well as endogenous CD5L production, were associated with reduced CD11b expression, increased IL-10 and PD-L1 production, and an enrichment of non-classical CD16+ monocytes. Analysis of the CD5L-dependent transcriptome in CD14 cells from RA patients revealed the acquisition of an efferocytosis profile, with upregulation of C1Q subunits, GAS6, AXL, and ALOX15B. It also showed signs of insufficient cargo processing, which dampens the resolution of inflammation, permits the expansion of IFN-primed non-classical monocytes, and correlates strongly with joint damage accrual. Despite markedly low CD5L levels in the synovium, RA synovial tissue was enriched with non-classical monocytes carrying the GAS6-AXL signature, which fosters osteoclast progenitors. In conclusion, this study demonstrates that the anti-inflammatory and inflammation-resolving properties of CD5L in experimental and human RA are mediated through the induction of efferocytosis-related and IFN-primed monocyte programs. This harbors a potential risk of uncontrolled invasion of non-classical monocytes into the synovial tissue, leading to joint structural damage. The complex role of CD5L in inflammation and disease outcomes requires careful consideration of the disease phase and experimental context.

immunology↗

bioRxiv2025

Insulin exerts epigenetic control of joint-specific memory T cells in rheumatoid arthritis

BackgroundInsulin has epigenetic effect influencing gene expression. High peripheral insulin concentrations promote insulin resistance in autoimmunity. Oncoprotein survivin/BIRC5 modulates glucose metabolism through chromatin binding and propagates IFNg effects in CD4+ cells. In this study, we explored how insulin influences chromatin binding and metabolic activity in autoimmune CD4+ cells of patients with rheumatoid arthritis (RA). MethodsWe profiled the metabolic activity of CD4+ cell clusters using single-cell transcriptome analysis in blood, synovial fluid and synovial tissue of RA patients. Through chromatin immunoprecipitation and sequencing, we identified the genes controlled by deposition of survivin and acetylated lysine 27 on histone H3 (H3K27ac) in CD4+ cells. Treating CD4+ cells with insulin and histone deacetylase inhibitors (HDACi), we identified changes in H3K27ac, linked those to transcription of the H3K27-survivin-controlled genes and the pathogenic phenotype of CD4+ cells using flow cytometry. Finally, we explored if anti-diabetic and anti-rheumatic drugs affect the metabolic profile and memory phenotype of the metabolic active CD4+ cells. ResultsTranscription of survivin/BIRC5 and histone acetylation enzymes strongly correlate with active metabolism in blood CD4+ cells of RA patients. In RA synovial tissue, these BIRC5hi active T cell clusters are inflammatory, exhausted, and memory-like. Genome co-deposition of H3K27ac-survivin pinpointed the insulin-dependent genes in metabolic active CD4+ cells. These genes favored histone acetylation by suppressing methylating enzymes EZH2 and KMT2A, and T cell development by activating CD27, CD3G, and SCIMP. Inhibition of histone deacetylation reverted these transcriptional effects and supported cellular sensitivity to insulin. Insulin stimulation increased H3K27ac and together with HDACi, suppressed PDCD1 and IFNg transcription and production in CD4+CD27+CD45RO+ memory T cells. Immune modulation impacted metabolic activity and synergized with the effect of histone acetylation on insulin responsiveness in RA patients. ConclusionsRA synovia is enriched with the metabolic active BIRC5hiCD4+ T cell clusters. The metabolic activity of these cells is histone acetylation-dependent and mediates insulin effects through the H3K27ac-survivin epigenetic mechanism. Increasing plasma insulin levels when combined with insulin sensitivity, can be protective in RA dearmoring effector T cell function. Hence, increasing the insulin sensitivity by enabling histone acetylation presents a reasonable interventional goal to restore immune cell homeostasis in RA.

immunology↗

bioRxiv2024

Survivin in synergy with BAF/SWI complex binds bivalent chromatin regions and activates DNA damage response in CD4+ T cells

This study explores a regulatory role of oncoprotein survivin on the bivalent regions of chromatin (BvCR) characterized by concomitant deposition of trimethylated lysine of histone H3 at position 4 (H3K4me3) and 27 (H3K27me3). Intersect between BvCR and chromatin sequences bound to survivin demonstrated their co-localization on cis-regulatory elements of genes which execute DNA damage control in primary human CD4+ cells. Survivin anchored BRG1-complex to BvCR to repress DNA damage repair genes in IFN{gamma}-stimulated CD4+ cells. In contrast, survivin inhibition shifted the functional balance of BvCR in favor of H3K4me3, which activated DNA damage recognition and repair. Co-expression of BRG1, survivin and IFN{gamma} in CD4+ cells of patients with rheumatoid arthritis identified arthritogenic BRG1hi cells abundant in autoimmune synovia. Immunomodulating drugs inhibited the subunits anchoring BRG1-complex to BvCR, which changed the arthritogenic profile. Together, this study demonstrates the function of BvCR in DNA damage control of CD4+ cells offering an epigenetic platform for survivin and BRG1-complex targeting interventions to combat autoimmunity. SummaryThis study shows that bivalent chromatin regions accommodate survivin which represses DNA repair enzymes in IFN{gamma}-stimulated CD4+ T cells. Survivin anchors BAF/SWI complex to these regions and supports autoimmune profile of T cells, providing novel targets for therapeutic intervention.

immunology↗

bioRxiv2022

Survivin prevents the Polycomb Repressor Complex 2 from methylating Histone 3 lysine 27

Survivin is a small protein that belongs to the inhibitor of apoptosis protein family and participates in cell division and apoptosis. It was actively studied in human cancers, inflammatory diseases and in autoimmune diseases. Here, we reveal that survivin takes part in epigenetic gene silencing by interaction with the polycomb repressive complex 2 (PRC2). PRC2 silences gene expression through tri-methylation of lysine 27 on histone 3 (H3K27). We detected differential expression of PRC2 core subunits in CD4+T cells with different survivin expression. ChIP-seq experiments indicated that survivin binds chromatin that overlap with the regions occupied by PRC2. ChIP-seq of H3K27 in CD4+T cells indicate that inhibition of survivin leads to a substantial increase in H3K27 tri-methylation by PRC2 in contrast to other histone modifications, which lends support to that survivin prevents PRC2 from functioning. Survivin binds peptides derived from PRC2 subunits EZH2, EED, SUZ12 and JARID2 in a peptide microarray that cover intersubunit interfaces, catalytic residues, and present binding sites for substrates, DNA, and regulatory proteins. Amino acid composition of the peptides has substantial predictive power for survivin interaction in the peptide microarray as determined by multilayer perceptron classification analysis. NMR experiments with 15N labelled survivin indicate that peptide colocalization does not entirely depend on binding mediated by short range interactions. These results indicate that survivin interacts with PRC2, preventing the methylation of H3K27 and specific gene silencing. This has transcriptional consequences and specific gene silencing.

molecular biology↗

bioRxiv2021

Chromatin binding of survivin regulates glucose metabolism in the IFN-g producing CD4+T cells

Interferon-gamma (IFN{gamma}) producing T cells develop metabolic adaptation required for their effector functions in tumour biology, autoimmunity and antiviral defence. Using sorted CD4+ cells we demonstrated that glycolytic switch and high glucose uptake in IFN{gamma}-producing cells was associated with survivin expression. Inhibition of survivin restored glycolysis by upregulating the transcription of phosphofructokinase PFKFB3 and reducing glucose uptake. Integration of the whole-genome sequencing of the chromatin immunoprecipitated with survivin with transcription changes in CD4+ cells after survivin inhibition revealed co-localization of survivin, IRF1 and SMAD3 in the regulatory elements paired to the differentially expressed genes. Western blot demonstrated direct binding of survivin to IRF1 and SMAD3. Functionally, inhibition of survivin repressed IFN{gamma} signalling and activated SMAD3-dependent protein remodelling, which resulted in the effector-to-memory transition of CD4+ cells. These findings demonstrate the key role of survivin in IFN{gamma}-dependent metabolic adaptation and identify survivin inhibition as an attractive strategy to counteract these effects.

immunology↗