Biology subjects

Juengst, C.

Publications and source records attributed to Juengst, C..

3 recordsLinked to original sources

bioRxiv2026

Atf3 Integrates Lipid and Cytoskeletal Remodeling to Drive Macrophage Fusion

Macrophages are highly plastic innate immune cells that can form multinucleated giant cells (MGCs) under physiological and pathological conditions, such as osteoclasts and foreign body giant cells. The mechanisms governing macrophage multinucleation remain incompletely understood. Here, we identify activating transcription factor 3 (Atf3) as an essential regulator of MGC formation via cell-cell fusion in response to persistent Interleukin 4 (IL-4) and STAT6 signaling, characteristic of the foreign body reaction. Atf3-deficient macrophages activate STAT6-dependent transcriptional programs in response to IL-4, including fusion-associated genes, yet fail to undergo multinucleation. This defect is associated with impaired actin cytoskeleton remodeling, abnormal nuclear morphology, reduced lamin A/C expression, and genome instability. Mechanistically, loss of Atf3 derepresses the Cholesterol-25-hydroxylase (Ch25h), elevating 25-hydroxycholesterol (25-HC), suppressing the mevalonate pathway, and reducing cholesterol and isoprenoid biosynthesis essential for cytoskeletal dynamics. Deletion of Ch25h in Atf3-deficient macrophages restores cholesterol levels and actin turnover, but not lamin A/C or fusion. These findings establish Atf3 as a central transcriptional node integrating lipid metabolism with cytoskeletal and nucleoskeletal remodeling to control IL-4-driven macrophage multinucleation.

cell biology↗

bioRxiv2025

Focal adhesion pathway inhibition is the central axis of macrophage phenotypic responses to monoclonal antibody therapy in aggressive lymphoma via high-throughput screening and high-content imaging

High-grade B-cell lymphoma (HGBCL) frequently arises as a refractory or relapsed state of diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes due to multi-drug resistance and hallmark oncogenic translocations. To identify novel therapeutic strategies, we developed a dual high-throughput screening (HTS) and high-content imaging (HCI) macrophage-tumour co-culture platform that quantifies antibody-dependent and antibody-independent cellular phagocytosis (ADCP/AICP) across a 1,241-compound library. Using GFP+ HGBCL cells and mCherry+ macrophages, we validated our methodology through time-resolved phenotypic profiling, Euclidean distance-based analysis, and hit compound prioritisation. Pathway interrogation revealed focal adhesion as a central hub of macrophage phenotypic modulation, highlighting focal adhesion kinase (FAK/PTK2) as a candidate therapeutic target. Pharmacological inhibition with PF-562271 enhanced phagocytic activity, altered macrophage morphology, and synergised with anti-CD20 monoclonal antibodies in vitro and ex vivo. In vivo, Rituximab plus PF-562271 significantly reduced lymphoma burden and prolonged survival in xenograft models. Collectively, our work demonstrates that HTS/HCI-driven phenotypic profiling of tumour-associated macrophages can uncover actionable therapeutic combinations and nominates FAK inhibition as a promising strategy to potentiate antibody immunotherapy in HGBCL.

cell biology↗

bioRxiv2020

Par3A and Par3B orchestrate podocyte architecture by regulating RhoA levels

Glomerular diseases are a major cause for chronic kidney disorders. In the majority of cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and subsequent loss of podocytes. Here, we establish a link between components of the Par3 polarity complex and actin regulators, which are necessary to establish and maintain the podocytes architecture utilizing both, mouse and Drosophila models. We demonstrate that the two mammalian Par3 proteins, Par3A and Par3B, share redundant functions despite differing in their ability to interact with other components of the Par complex. Only simultaneous inactivation of both Par3 proteins causes a severe disease phenotype in mouse podocytes by regulating Rho-GTP levels involving the actin regulators Synaptopodin and CD2AP in an aPKC independent manner.

cell biology↗