TY - JOUR AB - Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils “plucked” intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events. AU - Petzold, Tobias AU - Zhang, Zhe AU - Ballesteros, Iván AU - Saleh, Inas AU - Polzin, Amin AU - Thienel, Manuela AU - Liu, Lulu AU - Ul Ain, Qurrat AU - Ehreiser, Vincent AU - Weber, Christian AU - Kilani, Badr AU - Mertsch, Pontus AU - Götschke, Jeremias AU - Cremer, Sophie AU - Fu, Wenwen AU - Lorenz, Michael AU - Ishikawa-Ankerhold, Hellen AU - Raatz, Elisabeth AU - El-Nemr, Shaza AU - Görlach, Agnes AU - Marhuenda, Esther AU - Stark, Konstantin AU - Pircher, Joachim AU - Stegner, David AU - Gieger, Christian AU - Schmidt-Supprian, Marc AU - Gärtner, Florian R AU - Almendros, Isaac AU - Kelm, Malte AU - Schulz, Christian AU - Hidalgo, Andrés AU - Massberg, Steffen ID - 12119 IS - 12 JF - Immunity KW - Infectious Diseases KW - Immunology KW - Immunology and Allergy SN - 1074-7613 TI - Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease VL - 55 ER - TY - JOUR AB - Social distancing is an effective way to prevent the spread of disease in societies, whereas infection elimination is a key element of organismal immunity. Here, we discuss how the study of social insects such as ants — which form a superorganism of unconditionally cooperative individuals and thus represent a level of organization that is intermediate between a classical society of individuals and an organism of cells — can help to determine common principles of disease defence across levels of organization. AU - Cremer, Sylvia AU - Sixt, Michael K ID - 12133 IS - 12 JF - Nature Reviews Immunology KW - Energy Engineering and Power Technology KW - Fuel Technology SN - 1474-1733 TI - Principles of disease defence in organisms, superorganisms and societies VL - 22 ER - TY - JOUR AB - Reading, interpreting and crawling along gradients of chemotactic cues is one of the most complex questions in cell biology. In this issue, Georgantzoglou et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202103207) use in vivo models to map the temporal sequence of how neutrophils respond to an acutely arising gradient of chemoattractant. AU - Stopp, Julian A AU - Sixt, Michael K ID - 12272 IS - 8 JF - Journal of Cell Biology KW - Cell Biology SN - 0021-9525 TI - Plan your trip before you leave: The neutrophils’ search-and-run journey VL - 221 ER - TY - JOUR AB - When crawling through the body, leukocytes often traverse tissues that are densely packed with extracellular matrix and other cells, and this raises the question: How do leukocytes overcome compressive mechanical loads? Here, we show that the actin cortex of leukocytes is mechanoresponsive and that this responsiveness requires neither force sensing via the nucleus nor adhesive interactions with a substrate. Upon global compression of the cell body as well as local indentation of the plasma membrane, Wiskott-Aldrich syndrome protein (WASp) assembles into dot-like structures, providing activation platforms for Arp2/3 nucleated actin patches. These patches locally push against the external load, which can be obstructing collagen fibers or other cells, and thereby create space to facilitate forward locomotion. We show in vitro and in vivo that this WASp function is rate limiting for ameboid leukocyte migration in dense but not in loose environments and is required for trafficking through diverse tissues such as skin and lymph nodes. AU - Gaertner, Florian AU - Reis-Rodrigues, Patricia AU - De Vries, Ingrid AU - Hons, Miroslav AU - Aguilera, Juan AU - Riedl, Michael AU - Leithner, Alexander F AU - Tasciyan, Saren AU - Kopf, Aglaja AU - Merrin, Jack AU - Zheden, Vanessa AU - Kaufmann, Walter AU - Hauschild, Robert AU - Sixt, Michael K ID - 10703 IS - 1 JF - Developmental Cell SN - 1534-5807 TI - WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues VL - 57 ER - TY - THES AB - Detachment of the cancer cells from the bulk of the tumor is the first step of metastasis, which is the primary cause of cancer related deaths. It is unclear, which factors contribute to this step. Recent studies indicate a crucial role of the tumor microenvironment in malignant transformation and metastasis. Studying cancer cell invasion and detachments quantitatively in the context of its physiological microenvironment is technically challenging. Especially, precise control of microenvironmental properties in vivo is currently not possible. Here, I studied the role of microenvironment geometry in the invasion and detachment of cancer cells from the bulk with a simplistic and reductionist approach. In this approach, I engineered microfluidic devices to mimic a pseudo 3D extracellular matrix environment, where I was able to quantitatively tune the geometrical configuration of the microenvironment and follow tumor cells with fluorescence live imaging. To aid quantitative analysis I developed a widely applicable software application to automatically analyze and visualize particle tracking data. Quantitative analysis of tumor cell invasion in isotropic and anisotropic microenvironments showed that heterogeneity in the microenvironment promotes faster invasion and more frequent detachment of cells. These observations correlated with overall higher speed of cells at the edge of the bulk of the cells. In heterogeneous microenvironments cells preferentially passed through larger pores, thus invading areas of least resistance and generating finger-like invasive structures. The detachments occurred mostly at the tips of these structures. To investigate the potential mechanism, we established a two dimensional model to simulate active Brownian particles representing the cell nuclei dynamics. These simulations backed our in vitro observations without the need of precise fitting the simulation parameters. Our model suggests the importance of the pore heterogeneity in the direction perpendicular to the orientation of bias field (lateral heterogeneity), which causes the interface roughening. AU - Tasciyan, Saren ID - 12401 SN - 2663-337X TI - Role of microenvironment heterogeneity in cancer cell invasion ER -