Biology subjects

Nonn, O.

Publications and source records attributed to Nonn, O..

5 recordsLinked to original sources

bioRxiv2025

Interleukin-17A Mediates Cardiorenal Injury In Oxalate Nephropathy

AimsCardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). While CKD is known to give rise to systemic inflammation, its inciting factors remain poorly defined. Oxalate, long implicated in rare genetic kidney disorders, accumulates with decreased kidney function and has emerged as a driver of inflammation and independent risk factor for CVD. Here, we investigate the immunological mechanisms linking oxalate nephropathy to systemic inflammation, cardiac damage and kidney injury. Methods and ResultsOxalate nephropathy was induced in C57Bl6/N mice via an oxalate-enriched diet. Oxalate induced systemic immune activation, renal fibrosis, and cardiac remodeling, including pulmonary congestion with systolic and diastolic dysfunction. Flow cytometry analysis identified interleukin (IL)-17A as a dominant inflammatory effector, with expansion of Th17 and Th17-like Treg in the kidney, intestine, and spleen. Bulk mRNA sequencing confirmed these findings. Confirming the oxalate-IL-17A relationship, plasma IL-17A was elevated in patients with primary hyperoxaluria. Gut microbiome analysis by 16S amplicon sequencing showed only mild oxalate-induced alterations in mice. However, soluble oxalate directly enhanced Th17 polarization and disrupted mitochondrial respiration in vitro. In vivo, antibody-mediated (clone: 17F3) IL-17A blockade decreased cardiac fibrosis, reduced neutrophil infiltration, and partially restored cardiac function in oxalate-fed mice. ConclusionsOur study identifies oxalate as a systemic immunometabolic stressor and IL-17A as a central mediator of oxalate-induced cardiorenal injury. These findings establish the oxalate-IL-17A axis as a mechanistic link between CKD and CVD and suggest IL-17A inhibition as a potential therapeutic strategy to reduce cardiovascular damage in CKD. Translational PerspectiveThis study advances our understanding of targetable mediators of the cardiovascular risk in chronic kidney disease (CKD). We identify the organic anion oxalate, beyond its traditional role in crystal-induced kidney damage, as a systemic immunometabolic stressor. We demonstrate that oxalate induces IL-17A-mediated inflammation and thereby contributes to maladaptive cardiac remodeling. Therapeutic blockade of IL-17A protects against oxalate-induced cardiorenal injury, highlighting the oxalate-IL-17A axis as a relevant and druggable link between CKD and cardiovascular disease.

immunology↗

bioRxiv2025

TGFb-induced SMAD1/5 activation drives transient epithelial-to-mesenchymal transition in trophoblasts

Successful human placental development requires fetal trophoblasts to undergo epithelial-to-mesenchymal and mesenchymal-to-endothelial transitions, enabling invasion and remodeling of maternal spiral arteries for proper placental perfusion. These trans-differentiation processes are disrupted in preeclampsia, a major cause of maternal and fetal morbidity worldwide. Despite its clinical significance, the molecular mechanisms governing these differentiation trajectories at the fetal-maternal interface remain poorly defined. While Transforming Growth Factor-beta (TGF{beta}) has been implicated in trophoblast invasion, its role remains controversial. In this study, we report increased SMAD2/3 phosphorylation (pSMAD2/3), but reduced pSMAD1/5 and SNAIL levels in preeclamptic placentas. Mechanistically, we show that TGF{beta}1 induces transient SMAD1/5 phosphorylation via dual engagement of the TGF{beta} type I receptor ALK5 and the BMP type I receptor ALK2 in both HTR8/SVneo cells and human trophoblast stem cells. Moreover, single-nucleus transcriptomics of first-trimester placentas revealed co-expression of ACVR1, TGFBR1, SMAD1 and SMAD5 at the transition zone between cytotrophoblasts and extravillous trophoblasts. Our findings suggest that transient TGF{beta}-induced ALK5/ALK2-SMAD1/5 signaling is critical for EMT initiation, a prerequisite for proper placental differentiation.

molecular biology↗

bioRxiv2025

Maternal smoking in early pregnancy disrupts placental function through syncytiotrophoblast and macrophage dysregulation.

Smoking in pregnancy is the leading avoidable cause of gestational morbidity and mortality, causally linked to fetal growth restriction (FGR). The placenta, functional interface between mother and fetus is essential for healthy fetal development. For the first time, we studied cell type-resolved smoking effects on placental development at high molecular resolution using single-nucleus RNA sequencing and deep visual proteomics of matched tissues. We validated our findings through an independent cohort and in-vitro cigarette smoke exposure to primary human trophoblast cells. Our results show placental macrophages (Hofbauer cells; HBC) and the syncytiotrophoblast (STB) barrier are most affected by smoking, with dysregulation of cell-cell adhesion, extracellular matrix organization, and stress phenotype. STBs show moderate compositional increases in smokers and in-silico trophoblast differentiation modelling indicates a preferential shift towards the STB lineage in this group. The trophoblast displays a large upregulation of pro-angiogenic effectors, increases in xenobiotic detoxification, reduced mitochondrial function, and vastly altered transmembrane transport. These molecular changes affect placental development with important consequences for fetal growth. We provide insight into placental dysfunction contributing to FGR early in pregnancy, before clinical symptoms appear. We anticipate this data to advance diagnostics and therapies to improve FGR outcomes.

systems biology↗

bioRxiv2024

Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface

AimsThe gastrointestinal (GI) tract is composed of distinct subregions which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Method and ResultsHere, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF and were differentially expressed when compared to matched serum, all suggesting local synthesis. ConclusionCollection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of fecal samples or serum, providing direct insight into this understudied compartment.

microbiology↗

bioRxiv2022

Disturbed trophoblast transition links preeclampsia progression from placenta to the maternal syndrome

Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications1. We currently lack efficient screening tools2, 3 and early therapies4, 5 to address PE. To investigate the early stages of early onset PE, and identify candidate markers and pathways, we performed spatio-temporal multi-omics profiling of human PE placentae and healthy controls and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-seq approach combined with spatial proteo- and transcriptomics and mechanistic in vitro signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts. We found a significant increase in the senescence marker activin A in preeclamptic maternal serum in early gestation, before the development of clinical symptoms, indicating a translation of the placental syndrome to the maternal side. Our work describes a new disease progression, starting with a disturbed transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.

systems biology↗