Biology subjects

Maassen, S.

Publications and source records attributed to Maassen, S..

5 recordsLinked to original sources

bioRxiv2026

A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma

The bronchial epithelium in asthma is vulnerable to damage and has impaired barrier function, but the mechanisms by which it contributes to airway inflammation and remodelling remain unclear. Here, we dissect these epithelial and immunological disease mechanisms by establishing a comprehensive single cell atlas of the bronchial wall from 21 patients with childhood-onset asthma and 25 matched healthy controls. We identify a novel asthma-associated non-canonical epithelial differentiation trajectory in which a repair-associated KLF4+ basal cell subset differentiates into KRT13+ hillock-like cells through a proliferative KRT14+ intermediate. In vitro cultured matched primary bronchial epithelial cells show that this trajectory is retained in absence of exogenous factors. We find that IL-13 induces hillock-like cell differentiation into CEACAM5hi goblet cells, driving goblet cell metaplasia. Repair-associated basal cells and transitioning CEACAM5hi hillock-like cells strongly contribute to airway inflammation and remodelling. In turn, dendritic cells and mast cells promote a state of highly active epithelial differentiation, which shows increased multiciliated cell fate decisions, in concordance with an increase in multiciliated cell death observed in asthma. Proportions of the epithelial cells of the non-canonical differentiation trajectory are associated with clinical outcomes such as disease severity, FeNO, and small airway function.

immunology↗

bioRxiv2025

4-Hydroxynonenal suppresses IL-10 production during infection

Sepsis is a syndrome of life-threatening multiple organ failure induced by infection and hallmarked by the increased production of inflammatory cytokines and reactive oxygen species (ROS). The oxidation of lipids by ROS produces 4-hydroxynonenal (4-HNE), a highly reactive aldehyde that forms adducts with proteins and thereby impacts immune signaling. In this study, using blood samples from patients with sepsis at the emergency department, collected by the Acutelines data- and biobank, we show that 4-HNE selectively suppresses the production of the anti-inflammatory cytokine interleukin (IL)-10, while pro-inflammatory IL-6 and tumor necrosis factor (TNF)- are unaffected. Mechanistically, 4-HNE causes a pronounced transcriptional reorganization, leading to metabolic reprogramming and activation of HIF-1 signaling. In turn, this suppresses IL-10 production through inhibition of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-{kappa}B) signaling, whereas IL-6 and TNF- are unaffected due to increased activation of p38 mitogen-activated protein kinase (MAPK) signaling. This suppression likely occurs in sepsis, because, whereas overall 4-HNE protein adduct levels are increased in blood samples of sepsis patients, they are decreased in monocytes and T cells and negatively correlate with IL-10 levels. Thus, our data show that 4-HNE selectively suppresses IL-10 production in sepsis. This is likely relevant to the clinical outcome of sepsis patients because IL-10 levels correlate with mortality. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/690094v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@107d50dorg.highwire.dtl.DTLVardef@1344e23org.highwire.dtl.DTLVardef@f5f40borg.highwire.dtl.DTLVardef@16907e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

4-HNE reduces phagocytosis through the expression of Synaptotagmin 1 in human monocyte-derived macrophages

Reactive oxygen species (ROS) react with polyunsaturated fatty acids (PUFA) and generate the reactive aldehyde 4-hydroxynonenal (4-HNE). 4-HNE is a potent modulator of cell signaling, proliferation, and death. Our transcriptomics analysis revealed that upon treatment of human monocyte-derived macrophages with 4-HNE synaptotagmin-1 (SYT1), the main calcium sensor for neurotransmitter release, became the most strongly upregulated protein. This is surprising, as SYT1 expression is normally restricted to neurons and neuroendocrine cells. Using overexpression of SYT1 fused to a fluorescent reporter protein, we found SYT1 predominantly locates at the plasma membrane in macrophages. Based on this finding, and on the reported roles of other SYT forms in macrophages and other immune phagocytes, we tested the role of SYT1 in phagocytosis. Functional assays showed that SYT1 inhibited phagocytosis of pathogenic bacteria. Thus, our findings reveal an unexpected role of SYT1 in immune cells.

molecular biology↗

bioRxiv2023

Cofilin-Driven Nuclear Deformation Drives Dendritic Cell Migration through the Extracellular Matrix

To mount an adaptive immune response, dendritic cells must process antigens, migrate to lymph nodes and form synapses with T cells. Critical to 3D migration and mechano-sensing is the nucleus, which is the size-limiting barrier for navigation through gaps in the extracellular matrix. Here, we show that inflammatory activation of dendritic cells leads to the nucleus becoming spherically deformed, adopting a raison-like shape and enables dendritic cells to overcome the typical 2 - 3-micron pore limit for 3D-migration. We show that the nuclear shape-change is partially attained through reduced cell adhesion, whereas improved migration through extracellular matrix is achieved through reprogramming of the actin cytoskeleton. Specifically we show that cofilin-1 is phosphorylated at serine 41 drives the assembly of a Cofilin-ActoMyosin (CAM)-ring proximal to the nucleus and enhancing migration through 3D collagen gels. In summary, these data describe novel signaling events through which dendritic cells simultaneously deform their nucleus and enhance their migratory capacity; molecular events that may be re-capitulated in other contexts such as wound healing and cancer.

cell biology↗

bioRxiv2022

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T-cells accumulate cholesterol, which could lead to a pro-inflammatory phenotype. However, the role of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) in T-cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generated mice with T-cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T-cell Abca1/Abcg1-deficiency decreased blood, lymph node, and splenic T-cells, and increased T-cell activation and apoptosis. T-cell Abca1/Abcg1-deficiency induced a premature T-cell aging phenotype in middle-aged (12-13 months) Ldlr-/- mice, reflected by upregulation of senescence markers. Despite T-cell senescence and enhanced T-cell activation, T-cell Abca1/Abcg1-deficiency decreased atherosclerosis and aortic inflammation in middle-aged Ldlr-/- mice, accompanied by decreased T-cells in atherosclerotic plaques. We attribute these effects to T-cell apoptosis downstream of T-cell activation. Collectively, T-cell cholesterol efflux pathways are critical for maintaining T-cell numbers, suppress senescence, and induce atherosclerosis in middle-aged Ldlr-/- mice.

immunology↗