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Sabine Ameling

Publications and source records attributed to Sabine Ameling.

5 recordsLinked to original sources
PubMed2026

Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.

Pancreatitis is a life-threatening inflammatory disease of the pancreas. The cytokine interleukin-1α has been demonstrated to act as an alarmin released by necrotic cells. In the present study, we investigated the influence of IL-1α on the immune response during acute and chronic pancreatitis. Following tissue injury, pancreatic acinar cells released IL-1α, which activates tissue-resident fibroblasts to differentiate toward a pro-inflammatory phenotype. By secreting chemokines and cytokines such as CXCL5, CCL2, and IL-6, these fibroblasts recruit immune cells to the pancreas. The absence of IL-1α reduces disease severity in acute pancreatitis and chemokine release. Furthermore, IL-1α primes fibroblasts to enhance the production of extracellular matrix-components by the up-regulation of pro-fibrotic receptors such as Il4ra, Il13ra1, and Tgfbr3. Therefore, the deletion of IL-1α significantly reduced the development of tissue fibrosis. A therapeutic blockade of the IL1R1-signaling by i.p. administration of the IL-1-receptor antagonist Anakinra showed the same effect; the severity of acute pancreatitis and fibrogenesis during chronic pancreatitis were reduced. In conclusion, the crosstalk between necrotic acinar cells and fibroblasts mediated by IL-1α plays a crucial role in acute inflammation of the pancreas and fibrogenic signaling. Blockade of IL1R1-signaling by Anakinra is therefore a promising therapeutic intervention for both acute and chronic pancreatitis.

Anakinra↗
PubMed2026

Disease-driven post-transcriptional alterations and alternative splicing in podocytes in focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and progression to end-stage renal disease, yet its molecular pathogenesis remains still incompletely defined. While transcriptional alterations in podocytes have been extensively characterized, the contribution of post-transcriptional regulatory mechanisms is poorly understood. Here, we combined a zebrafish podocyte-specific injury model with glomerulus-resolved transcriptomic profiling to dissect RNA regulatory alterations during FSGS progression. Integrated analyses of bulk RNA sequencing, small RNA profiling, and alternative splicing revealed pronounced, time-dependent remodeling of the glomerular transcriptome. We demonstrate that podocyte injury is associated with loss of key podocyte-specific proteins, activation of inflammatory pathways, remodeling of the extracellular matrix, and altered microRNA expression, such as miR-21 and miR-193. Moreover, we found that alternative splicing influences key podocyte gene expression, affecting genes critical for slit diaphragm integrity, actin cytoskeleton organization, and glomerular basement membrane stability. Isoform analyses identified FSGS-associated isoform switches in SRSF3 and EPB41L5. Importantly, these changes were also evident in glomeruli from FSGS patients, demonstrating that the zebrafish model recapitulates key molecular features of human disease and highlighting alternative splicing as a central regulatory mechanism in FSGS.

Animals↗
PubMed2026

Determinants of pro- and anti-inflammatory cytokine profiles across populations.

BACKGROUND: Cytokine dysregulation contributes to chronic inflammation and immune-mediated diseases, yet population-level determinants of pro- and anti-inflammatory cytokines remain poorly characterized. We aimed to identify demographic and lifestyle determinants of plasma cytokine levels and evaluate reproducibility of inflammatory patterns across European populations. METHODS: In the population-based Rotterdam Study cohort (n&#x2009;=&#x2009;3,456; mean age 57 years; 56% female), we examined associations between plasma levels of nine cytokines (Olink Inflammation Panel) and age, sex, smoking, body mass index (BMI), and alcohol consumption. Linear and non-linear regression models were applied, with stratified analyses where appropriate. Cytokine clustering was assessed using principal component analysis (PCA). Findings were replicated in two independent European cohorts using identical protocols. Additionally, associations between raw IL-6 levels and determinants were meta-analyzed across the two replication cohorts (total n&#x2009;>&#x2009;4,000). RESULTS: Plasma IL-10, IL-6, IL-17&#xa0;A, TNF, IFN-&#x3b3;, IL-18, and IL-17&#xa0;C increased with age; IL-18 and IL-17&#xa0;C followed non-linear trends (P < 0.01). Females had lower IL-18 and IL-17&#xa0;C levels (&#x3b2;: -&#x2009;0.41 and -&#x2009;0.32, respectively) but higher IFN-&#x3b3; (&#x3b2;: 0.17). Smoking was associated with higher IL-10, IL-6, IL-18, and IL-17&#xa0;C (&#x3b2; range: 0.10-0.54) and lower IFN-&#x3b3; (&#x3b2;: -0.15) and IL-13 (&#x3b2;: -&#x2009;0.10). BMI was positively associated with IL-6, IL-18, TNF, and IL-17&#xa0;A levels (P < 0.05), and inversely with IL-10 (P < 0.001). Sex-specific associations were observed for alcohol use. PCA revealed stable pro-inflammatory cytokine clustering, consistent across cohorts. Replication in analyses confirmed a robust, shared pro-inflammatory signature, and meta-analysis supported consistent associations with older age, higher BMI, and current smoking. CONCLUSIONS: Older age, higher BMI, male sex, and current smoking are consistent and reproducible determinants of inflammatory cytokine profiles across European populations. These findings support the use of cytokine profiling in enhancing risk stratification for inflammation-related diseases.

Humans↗
PubMed2025

Circulating miRNAs and inflammatory markers - Associations between miRNAs and cytokine levels point to miRNA-mediated sCD40L release from platelets.

MicroRNAs (miRNAs) are gaining increasing attention, particularly because of their involvement in immune-related signaling pathways. We investigated the association between 179 plasma-circulating miRNAs (Plasma Focus microRNA PCR Panel) and 47 cytokines ("MILLIPLEX&#xae; panel) in 692 participants of the population-based SHIP-TREND cohort (age range 21-79) and two additional cohorts to present a comprehensive map of miRNA-cytokine relations. Multivariate linear regression models identified Bonferroni-corrected significant associations between miRNAs and cytokines for EGF (pro-epidermal growth factor), PDGF-AA, PDGF-AB/BB (platelet-derived growth factor subunit A and B), VEGF-A (vascular endothelia growth factor A), and sCD40L (soluble CD40 ligand) with sCD40L showing the most robust pattern. These models were adjusted for age, sex, platelet count, BMI, smoking, and technical parameters. In the follow-up sample (N&#xa0;=&#xa0;191, 7&#xa0;years after initial sampling), we confirmed that the observed associations were stable over time and replicated our findings in an independent clinical cohort (N&#xa0;=&#xa0;74). Furthermore, the causal mediation results provide evidence for the involvement of platelet activity in the regulation of sCD40L mediated by five miRNAs in the range of 25&#xa0;%-69&#xa0;% of the effect being mediated (strongest mediation for hsa-miR-223-3p). Our study highlights a strong and stable miRNA-mediated modulation of sCD40L, at the stage of platelet activation with potential subsequent effects on the interaction of immune cells and haemostasis pointing to a complex regulatory mechanism. Future research is needed to determine the clinical relevance of our observations in the context of vascular thrombosis, immunological disorders, and neurodegeneration.

Humans↗
PubMed2025

Alternative Splicing in Mechanically Stretched Podocytes as a Model of Glomerular Hypertension.

KEY POINTS: Mechanical stretch induced over 3000 alternative splicing events in podocytes, affecting gene expression and protein abundance. Seventeen genes showed consistent splicing events across multiple analysis tools, with key isoform changes. Shroom3 and Myl6 underwent isoform switches under mechanical stretch, altering the C-terminal sequence and interaction properties of Myl6. BACKGROUND: Alterations in pre-mRNA splicing are crucial to the pathophysiology of various diseases. However, the effects of alternative splicing of mRNA on podocytes in hypertensive nephropathy are still unknown. The Sys_CARE project aimed to identify alternative splicing events involved in the development and progression of glomerular hypertension. METHODS: Murine podocytes were exposed to mechanical stretch, after which proteins and mRNA were analyzed by proteomics, RNA sequencing, and several bioinformatic alternative splicing tools. RESULTS: Using transcriptomic and proteomic analysis, we identified significant changes in gene expression and protein abundance because of mechanical stretch. RNA-Seq identified over 3000 alternative spliced genes after mechanical stretch, including all types of alternative splicing events. Among these, 17 genes exhibited an alternative splicing event across four different splicing analysis tools. From this group, we focused on Myl6, a component of the myosin protein complex, and Shroom3, an actin-binding protein essential for podocyte function. We identified two Shroom3 isoforms with significant expression changes under mechanical stretch, which was validated by quantitative RT-PCR and in situ hybridization. In addition, we observed an expression switch of two Myl6 isoforms after mechanical stretch, accompanied by an alteration in the C-terminal amino acid sequence. CONCLUSIONS: A comprehensive RNA-Seq analysis of mechanically stretched podocytes identified novel potential podocyte-specific biomarkers and highlighted significant alternative splicing events, notably in the mRNA of Shroom3 and Myl6.

podocyte↗