Biology subjects

Ettel, P.

Publications and source records attributed to Ettel, P..

3 recordsLinked to original sources

bioRxiv2026

A cell death screen identifies macrophage-depleting agents with therapeutic potential

Macrophages are critical regulators of inflammation and tissue homeostasis, yet aberrant macrophage activation contributes to a wide spectrum of inflammatory and malignant diseases. Therapeutic strategies that directly reduce macrophage numbers have shown promise, but macrophage survival pathways remain incompletely defined, limiting the development of targeted therapeutic strategies. Here, we establish a high-throughput screening platform to identify small molecule inhibitors that impair macrophage survival. Screening a library of more than 2,000 targeted compounds in a cell survival assay, combined with in silico and in vitro analysis of macrophage specificity, revealed the identification of three potent inhibitors: BIX-01294, GSK-J4, and Masitinib. All three compounds downregulated leukemia inhibitory factor receptor (LIFR), whose inhibition markedly reduced macrophage viability. In vivo, these inhibitors effectively depleted large peritoneal macrophages, ameliorated key symptoms of macrophage activation syndrome (MAS), and suppressed tumor growth in a syngeneic transplanted melanoma model as well as in an autochthonous lung cancer model. Together, these findings identify small molecule-mediated macrophage depletion as a promising therapeutic strategy and establish an experimental approach to uncover regulators of macrophage survival.

immunology↗

bioRxiv2026

Stress-induced Metabolic Remodeling of Adipose and Brain Tissue revealed by Positron Emission Tomography

Stress impacts our health and triggers physiological adaptations, yet the metabolic programs engaged during stress remain incompletely understood. To fill this knowledge gap, we utilized total-body positron emission tomography (PET), multi-OMICS, and endocrine profiling to assess how various murine stress models affect systemic metabolic remodeling. We found that acute immobilization and surgery activate brown adipose tissue as part of the stress response, independently of hypothermia, thereby acting as a highly stress-sensitive metabolic hub. Additionally, we identified stress-specific hypo- and hypermetabolic signatures in different brain regions, and distinguished networks between brain and adipose tissue depots across the different stress groups. Our work presents a novel perspective on stress and its mobilization of metabolic resources and identifies PET imaging of brain and adipose tissue as a valuable, minimally invasive technique for tracking metabolic stress responses in mice, with relevance for animal welfare and disease models, and translational impact for mental health studies and preventive medicine.

physiology↗

bioRxiv2025

IRF4 is a master regulator of multinucleated giant cell formation

Multinucleated giant cells (MGCs) are a hallmark pathological feature of a wide range of diseases, yet the mechanisms underlying their formation and function remain poorly understood. Although it is recognized that MGCs arise from a heterogeneous pool of myeloid precursors, how a committed MGC fate develops therein remains unknown. Here, combining temporal in vitro and in vivo differentiation of bone marrow-derived myeloid precursors with single cell and bulk RNA sequencing as well as CRISPR/Cas9-mediated gene editing, we shed insight into how MGCs emerge. Our findings reveal that coordinated upregulation of cell fusion genes and cellular metabolism, particularly oxidative phosphorylation, regulate the transition from macrophage progenitors to fusion competent cells. In vivo fate-mapping unveils Ms4a3-, and Cd11c-but not Cx3cr1-traced cells as the predominant precursor populations for MGCs in a lung granuloma formation model. Notably, transcription factor profiling in the progression from early myeloid precursors to pre-MGCs identifies IRF4 as a key molecular switch driving MGC generation. IRF4+ MGCs are present in different pathologies, including Schistosoma mansoni egg induced granulomas, Aspergillus fumigatus conidia mediated allergic airway inflammation and human head and neck squamous cell carcinomas. Mechanistically, IRF4 controls critical fusion related genes such as Dcstamp and Ocstamp. Consequently, Irf4 deficient cells are unable to develop into MGCs. Collectively, our work delineates the trajectory of MGC differentiation, establishing IRF4 as a defining transcription factor required for the generation of fusion-competent progenitors that ultimately give rise to MGCs.

immunology↗