Biology subjects

Mertens, C.

Publications and source records attributed to Mertens, C..

3 recordsLinked to original sources

bioRxiv2026

Liver sinusoidal endothelial cells integrate metabolic and immune signals for MAPK-dependent BMP6 regulation and hepcidin induction

Liver sinusoidal endothelial cells (LSECs) separate the blood from the hepatic parenchyma and thus are at the frontline as scavengers of blood-borne waste, pathogens and metabolic stimuli. LSECs are also critical for sensing systemic iron availability by controlling the synthesis of bone morphogenetic protein (BMP) 6, which is essential for hepcidin expression in hepatocytes. Hepcidin maintains systemic iron homeostasis by inhibiting dietary iron uptake and iron release from iron recycling macrophages. Hepcidin is also an acute-phase protein and its activation by inflammation requires active BMP signaling. It is incompletely understood how signals derived from inflammation, cellular damage and iron are integrated by the liver to assure adequate hepcidin expression. Here, we show that Bmp6 expression is activated in primary LSEC cultures upon their exposure to damage-associated molecular patterns (DAMPs), such as heme and myoglobin, pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and Fibroblast-Stimulating Lipopeptide-1 (FSL1), or oxidative stress inducers (H2O2). All regulatory cues converge at the MAPK signaling pathway, although the specific signaling branches involved are stimulus-specific. Notably, Bmp6 upregulation in LSECs in response to all signals tested is strongly enhanced by the hepatocyte secretome. As hepatocytes critically depend on active BMP/SMAD signaling to control hepcidin activation, our results reveal that multiple sources of signaling input activating Bmp6 in LSECs and hepcidin in hepatocytes serve to determine BMP/SMAD signaling strength. Furthermore, our findings identify hypoferremia, the result of high hepcidin levels due to elevated Bmp6, as a convergent response in conditions of inflammation, oxidative stress and cellular damage. HighlightsO_LIDAMPs (heme and myoglobin), PAMPs (LPS) and oxidative stress activate Bmp6 mRNA expression via the MAPK signaling pathway C_LIO_LIThe TLR/MAPK/BMP6 regulatory axis integrates inflammatory and iron signals C_LIO_LIOur work uncovers a novel connection between innate immune sensing, oxidative stress and hepatic iron homeostasis C_LI

cell biology↗

bioRxiv2024

Glutaredoxin 3 (GLRX3) confers a fusion oncogene-dependent vulnerability to Ewing sarcoma

Ewing sarcoma (EwS) is a highly aggressive bone and soft-tissue associated cancer for which there are no effective targeted therapeutics available. Genetically, EwS is driven by aberrantly active EWSR1::ETS fusion transcription factors, most commonly EWSR1::FLI1. Despite their unique expression in EwS, all attempts to effectively target these fusion oncoproteins clinically were not yet successful, wherefore alternative targets are required. Here, we functionally characterize the evolutionarily conserved oxidative stress regulator glutaredoxin 3 (GLRX3) as a EwS-specific and EWSR1::FLI1-dependent vulnerability. Through integration of transcriptome-profiling, conditional drug screens in 3D cultures, and functional experiments, we discover that GLRX3 promotes EwS growth in vitro and in vivo, and that it has a key role in mitigation of oxidative stress and maintenance of iron homeostasis. These GLRX3 functions can be exploited in both GLRX3-high and -low expressing EwS cells by targeted therapeutics including CDK4/6 inhibitors and inducers of apoptotic and ferroptotic cell death. Collectively, our results exemplify how the interplay of an evolutionarily conserved oxidative stress regulator with a dominant oncogene can promote malignancy but provide opportunities for predictive diagnostics and personalized therapy.

cancer biology↗

bioRxiv2020

Streptococcus pneumoniae serotypes carried by young children and their association with Acute Otitis Media during the period 2016 - 2019.

BackgroundStreptococcus pneumoniae (Sp) is a major cause of acute otitis media (AOM). Pneumococcal conjugate vaccine (PCV) programs have altered pneumococcal serotype epidemiology in disease and carriage. To establish the clinical picture of AOM in young children exposed to the PCV program in Belgium and the Sp strains they carry, a cross-sectional study started in 2016. Material/methodsIn three collection periods from February 2016 to May 2018, nasopharyngeal swabs and background characteristics were collected from children aged 6-30 months either presenting at their physician with AOM (AOM-group) or healthy and attending day care (DCC-group). Sp was detected, quantified, and characterized using both conventional culture and qPCR. Clinical signs of AOM episodes and treatment were registered by the physicians. ResultsAmong 3264 collected samples, overall pneumococcal carriage and density were similar in AOM (79.2% and 0.50 x106 copies/l) and DCC (77.5% and 0.42 x106 copies/l). Non-vaccine serotypes were most frequent: 23B (AOM: 12.3%; DCC: 17.4%), 11A (AOM: 7.5%; DCC: 7.4%) and 15B (AOM: 7.5%; DCC: 7.1%). Serotypes 3, 6C, 7B, 9N, 12F, 17F and 29 were more frequent in AOM than in DCC, whereas 23A and 23B frequencies were lower. Antibiotic susceptibility of Sp strains was similar in both groups . No predictors of AOM severity were identified, and 77.3% received an antibiotic prescription. ConclusionYoung children with AOM did not carry Sp more frequently or at higher load than healthy children in day care, but some ST were more frequent in AOM and are not included in the currently used vaccines.

immunology↗