Biology subjects

Zwicky, P.

Publications and source records attributed to Zwicky, P..

4 recordsLinked to original sources

bioRxiv2025

Mapping Leukocyte Dynamics during Neuroinflammation Identifies Meningeal Monocyte-Derived Macrophages as Drivers of Progressive Disease

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by increasing disability. The cellular and molecular drivers of clinical transition towards progressive disease are poorly understood. Here, we combine single-cell profiling technologies with genetic and pharmacological perturbations across the course of murine CNS inflammation to dissect the role of the local immune landscape in disease progression. We uncover a chronic monocyte-to-phagocyte transition as a hallmark of progressive disease, characterized by the emergence of maladaptive, lipid-associated macrophages (LAMs) marked by lysosomal activation and fibrotic features. Spatial transcriptomics and multiplexed imaging revealed that these LAMs localized to the leptomeninges in close proximity to parenchymal colony-stimulating factor (CSF)-1 producing disease-associated microglia (DAMs) and meningeal granulocyte-macrophage (GM)-CSF-expressing T helper cells that license their differentiation. Interference with this local cytokine network revealed a protective role for resident microglia and implicated monocyte-derived phagocytes as key drivers of progressive neuroinflammation. Notably, LAM-like macrophages could also be identified in the meninges of people with MS, indicating a homology to human disease. By elucidating their ontogeny, spatial niche, and regulatory cytokine milieu, we provide a mechanistic framework for targeting harmful myeloid states while preserving reparative CNS immunity in progressive MS.

immunology↗

bioRxiv2025

Sensitizing Immune-Refractory Ovarian Tumors via p53 Mutation-Tailored Immunotherapy

High-grade serous ovarian cancer demonstrates limited responsiveness to immune checkpoint inhibitors, owing in part to immunosuppressive environments shaped by nearly universal p53 aberrations. Utilizing an immunocompetent mouse model and individual p53 mutations, we identified a dependence of the p53-R270H mutation (equivalent of human R273H) on regulatory T cells (Tregs) and the PD-1/PD-L1 axis. Analysis of patient datasets associated R273H with elevated levels of two p53 targets, PD-L1 and amphiregulin (AREG), a Tregs growth factor. In contrast to p53-R172H tumors, where there was limited activity, dual antibody therapy targeting AREG and PD-L1 selectively and effectively inhibited R270H tumors. This involved polarization toward M1 macrophages, infiltration of CD8+ T cells, diminished Ly6G+ neutrophils and downregulation of interleukin-4. In patient-derived R273C organoids, the combination treatment reduced the CD4/CD8 ratio. This study is the first to establish a mutation-tailored therapeutic approach that leverages the capacity of p53 to modulate immunosuppressive mechanisms.

cancer biology↗

bioRxiv2024

Targeted CRISPR-Cas9 screening identifies transcription factor network controlling murine haemato-endothelial fate commitment

Haematopoiesis is a tightly coordinated process that forms and maintains all blood cells. During development blood generation begins in the yolk sac with the differentiation of haemato-endothelial mesoderm giving rise to haematopoietic progenitors. Which molecular regulators are crucial for haemato-endothelial mesoderm formation remains unclear and has not been studied in an unbiased way. Here we employ a mouse embryonic stem cell model that recapitulates embryonic blood development and perform targeted CRISPR-Cas9 knock out screens focusing on transcription factors and chromatin regulators. Focusing on the transition of primitive towards haematoendothelial mesoderm we identified the known master regulator Etv2 and novel transcription factors including Smad1, Ldb1, Six4 and Zbtb7b acting as crucial drivers or repressors of mesodermal commitment. Our transcriptome analysis highlights that each factor has a precise impact on the gene expression signature of the developing mesoderm resulting in the formation of mesodermal subsets with a defined lineage differentiation bias. Our study reveals novel molecular pathways governing mesodermal development crucial to allow endothelial and haematopoietic lineage specification.

developmental biology↗

bioRxiv2023

Epidermal barrier dysregulation in atopic skin predisposes for excessive growth of the allergy-associated yeast Malassezia

The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of the barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While sensitisation to Malassezia, the most abundant commensal fungus of the skin, is common in AD, its relevance for pathogenesis remains unclear. Here we show that in barrier-disrupted skin, Malassezia acquires enhanced fitness. This is not a consequence of the dysregulated allergic immune status characteristic for AD but is rather explained by structural and metabolic changes in the cutaneous niche that provide increased accessibility and a favourable lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. These findings reveal fundamental insights into the role of the mycobiota in the pathogenesis of common skin barrier disorders.

microbiology↗