Biology subjects

Sieweke, M.

Publications and source records attributed to Sieweke, M..

4 recordsLinked to original sources

bioRxiv2026

Stroke-induced lipocalin-2-expressing red pulp macrophages reprogram peripheral immunity

Acute ischemic stroke (AIS) induces profound systemic immune alterations that contribute to infection susceptibility. Here, we identify lipocalin-2 (LCN-2) as a rapidly induced and conserved regulator of stroke-associated immunosuppression. Using 3-MACE-Seq, cytokine profiling, and immunofluorescence in C57BL/6J mice subjected to transient middle cerebral artery occlusion (tMCAO), we show that LCN-2 is strongly upregulated in splenic red pulp macrophages (RPMs) within 24 hours and again 7 days post-tMCAO. LCN-2-expressing RPMs form immunological synapses with CD3+ T cells, thereby impacting T cell trafficking. Recombinant LCN-2 directly reprogrammed T cells and monocytes toward hyporesponsive, tolerogenic phenotypes by suppressing inflammatory cytokines, impairing chemotaxis, enhancing phagocytosis, and uncoupling oxidative burst. Human spleens likewise displayed LCN-2-expressing CD68+ RPMs, and LCN-2 preconditioning of monocytes reproduced reduced HLA-DR, CD80, CD206, and ROS with increased uptake of E. coli bioparticles. These findings identify LCN-2 signaling as a central orchestrator of stroke-induced peripheral immunoreprogramming and a potential therapeutic target to mitigate post-stroke immunodepression. SummaryAcute ischemic stroke induces LCN-2 in splenic red pulp macrophages, which reprogram T cells and monocytes toward tolerogenic, hyporesponsive states. Mouse and human data identify LCN-2 as a driver of peripheral immunodepression and a potential target to reduce infection risk. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/733904v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@fb0caforg.highwire.dtl.DTLVardef@1fdcd41org.highwire.dtl.DTLVardef@1ae99b0org.highwire.dtl.DTLVardef@1ec0837_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

immunology↗

bioRxiv2024

Epromoters bind key stress-related transcription factors to regulate clusters of stress response genes

Stress insults trigger the rapid and global reprogramming of gene transcription by coordinated recruitment of a limited number of key inducible transcription factors to cis-regulatory elements. Here, we performed a comprehensive analysis of different stress models and observed that co-induced genes are generally located in close genomic proximity. By integrating gene expression and transcription factor binding resources in different stress models, we found an enrichment for clusters whereby only one of the promoters of the cluster recruits the key transcription factors, reminiscent of Epromoters, a type of cis-regulatory elements displaying both promoter and enhancer function. Epromoter-regulated clusters were frequently found irrespectively of the stress or inflammatory response. Predicted Epromoters displayed enhancer activity and regulated clusters of stress-response genes independently of their genomic location. These findings have significant implications for understanding complex gene regulation following the response to acute perturbations. TeaserWhen cells face stress, they undergo rapid changes in gene expression, orchestrated by a handful of key transcription factors. But how do these factors coordinate such a complex response? Our study reveals that "Epromoters"--cis-regulatory elements that combine the functions of both promoters and enhancers help organize stress-response genes into tightly regulated clusters. This discovery not only deepens our understanding of gene regulation in the face of stress but also offers exciting implications for studying inflammation and other acute cellular responses.

genomics↗

bioRxiv2024

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer's disease

This study explores the influence of lifestyle on Alzheimers disease (AD) progression using App-NL-G-F mice in a complex enrichment system. Mice exhibited social deficits before plaque pathology or memory impairment, revealing a crucial link between lifestyle, behavior, and neuroinflammation. Plasma analysis indicates early inflammation and apoptosis-related changes, setting the stage for identifying markers predicting plaque manifestation. Beyond pathology, social behavior is linked to adult neurogenesis and microglia coverage, forming a dynamic connection with microglia activation. Further, sc-RNA sequencing unveiled a decrease in interferon-responsive microglia and alteration in antigen processing with enrichment. These findings underscore the beneficial impact of social housing on microglia and interconnected factors, pointing to microglia as a critical mediator of the behavior-pathology-plasticity interplay in AD. The study enhances our understanding of AD complexity and offers insights into potential therapeutic strategies, emphasizing the multifaceted nature of AD progression and the role of lifestyle in shaping its course.

neuroscience↗

bioRxiv2021

CD150-dependent hematopoietic stem cells sensing of Brucella instructs myeloid commitment

So far, hematopoietic stem cells (HSC) are considered the source of mature immune cells, the latter being the only ones capable of mounting an immune response. Recent evidence shows HSC can also directly sense cytokines released upon infection/inflammation and pathogen-associated molecular pattern interaction, while keeping a long-term memory of previous encountered signals. Direct sensing of danger signals by HSC induces early myeloid commitment, increases myeloid effector cell numbers and contributes to an efficient immune response. Here, using specific genetic tools on both host and pathogen sides, we show that HSC can directly sense B. abortus pathogenic bacteria within the bone marrow via the interaction of the cell surface protein CD150 with the bacterial outer membrane protein Omp25, inducing efficient functional commitment of HSC to the myeloid lineage. This is the first demonstration of a direct recognition of a live pathogen by HSC via CD150, which attests of a very early contribution of HSC to immune response. SUMMARYThis work provides first evidence HSC directly sense Brucella abortus via the bacterial outer membrane protein Omp25 and the HSC surface receptor CD150, leading to functional commitment of HSC to myeloid lineage and very early initiation of immune response.

immunology↗