@article{17191, abstract = {Dendritic cells migrate to and from lymph nodes in response to chemokine gradients.Data now show that steady-state migration of these cells can be triggered by a mechanosensitive pathway.}, author = {Lembo, Sergio and Sixt, Michael K}, issn = {1529-2916}, journal = {Nature Immunology}, pages = {1131–1132 }, publisher = {Springer Nature}, title = {{Nuclear squeezing wakes up dendritic cells}}, doi = {10.1038/s41590-024-01881-2}, volume = {25}, year = {2024}, } @article{17233, abstract = {CRISPR-Cas9 technology has become an essential tool for plant genome editing. Recent advancements have significantly improved the ability to target multiple genes simultaneously within the same genetic background through various strategies. Additionally, there has been significant progress in developing methods for inducible or tissue-specific editing. These advancements offer numerous possibilities for tailored genome modifications. Building upon existing research, we have developed an optimized and modular strategy allowing the targeting of several genes simultaneously in combination with the synchronized expression of the Cas9 endonuclease in the egg cell. This system allows significant editing efficiency while avoiding mosaicism. In addition, the versatile system we propose allows adaptation to inducible and/or tissue-specific edition according to the promoter chosen to drive the expression of the Cas9 gene. Here, we describe a step-by-step protocol for generating the binary vector necessary for establishing Arabidopsis edited lines using a versatile cloning strategy that combines Gateway® and Golden Gate technologies. We describe a versatile system that allows the cloning of as many guides as needed to target DNA, which can be multiplexed into a polycistronic gene and combined in the same construct with sequences for the expression of the Cas9 endonuclease. The expression of Cas9 is controlled by selecting from among a collection of promoters, including constitutive, inducible, ubiquitous, or tissue-specific promoters. Only one vector containing the polycistronic gene (tRNA-sgRNA) needs to be constructed. For that, sgRNA (composed of protospacers chosen to target the gene of interest and sgRNA scaffold) is cloned in tandem with the pre-tRNA sequence. Then, a single recombination reaction is required to assemble the promoter, the zCas9 coding sequence, and the tRNA-gRNA polycistronic gene. Each element is cloned in an entry vector and finally assembled according to the Multisite Gateway® Technology. Here, we detail the process to express zCas9 under the control of egg cell promoter fused to enhancer sequence (EC1.2en-EC1.1p) and to simultaneously target two multiple C2 domains and transmembrane region protein genes (MCTP3 and MCTP4, respectively at3g57880 and at1g51570), using one or two sgRNA per gene.}, author = {Li, Ziqiang and Huard, Jennifer and Bayer, Emmanuelle M. and Wattelet-Boyer, Valérie}, issn = {2331-8325}, journal = {Bio-protocol}, number = {13}, publisher = {Bio-Protocol}, title = {{Versatile cloning strategy for efficient multigene editing in Arabidopsis}}, doi = {10.21769/BioProtoc.5029}, volume = {14}, year = {2024}, } @article{17279, abstract = {In a recent issue of Cell, Zhang et al.1 demonstrate that mechanical features of a solid tumor can drive T cells into dysfunctionality and identify pathways that revert this “exhausted” state.}, author = {Avellaneda Sarrió, Mario and Sixt, Michael K}, issn = {2451-9448}, journal = {Cell Chemical Biology}, number = {7}, pages = {1242--1243}, publisher = {Elsevier}, title = {{Rescuing T cells from stiff tumors}}, doi = {10.1016/j.chembiol.2024.06.011}, volume = {31}, year = {2024}, } @article{17284, abstract = {Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.}, author = {Gärtner, Florian R and Ishikawa-Ankerhold, Hellen and Stutte, Susanne and Fu, Wenwen and Weitz, Jutta and Dueck, Anne and Nelakuditi, Bhavishya and Fumagalli, Valeria and Van Den Heuvel, Dominic and Belz, Larissa and Sobirova, Gulnoza and Zhang, Zhe and Titova, Anna and Navarro, Alejandro Martinez and Pekayvaz, Kami and Lorenz, Michael and Von Baumgarten, Louisa and Kranich, Jan and Straub, Tobias and Popper, Bastian and Zheden, Vanessa and Kaufmann, Walter and Guo, Chenglong and Piontek, Guido and Von Stillfried, Saskia and Boor, Peter and Colonna, Marco and Clauß, Sebastian and Schulz, Christian and Brocker, Thomas and Walzog, Barbara and Scheiermann, Christoph and Aird, William C. and Nerlov, Claus and Stark, Konstantin and Petzold, Tobias and Engelhardt, Stefan and Sixt, Michael K and Hauschild, Robert and Rudelius, Martina and Oostendorp, Robert A.J. and Iannacone, Matteo and Heinig, Matthias and Massberg, Steffen}, issn = {1476-4687}, journal = {Nature}, pages = {645--653}, publisher = {Springer Nature}, title = {{Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis}}, doi = {10.1038/s41586-024-07671-y}, volume = {631}, year = {2024}, } @article{18109, abstract = {Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.}, author = {Stark, Konstantin and Kilani, Badr and Stockhausen, Sven and Busse, Johanna and Schubert, Irene and Tran, Thuy Duong and Gärtner, Florian R and Leunig, Alexander and Pekayvaz, Kami and Nicolai, Leo and Fumagalli, Valeria and Stermann, Julia and Stephan, Felix and David, Christian and Müller, Martin B. and Heyman, Birgitta and Lux, Anja and Da Palma Guerreiro, Alexandra and Frenzel, Lukas P. and Schmidt, Christoph Q. and Dopler, Arthur and Moser, Markus and Chandraratne, Sue and Von Brühl, Marie Luise and Lorenz, Michael and Korff, Thomas and Rudelius, Martina and Popp, Oliver and Kirchner, Marieluise and Mertins, Philipp and Nimmerjahn, Falk and Iannacone, Matteo and Sperandio, Markus and Engelmann, Bernd and Verschoor, Admar and Massberg, Steffen}, issn = {1097-4180}, journal = {Immunity}, number = {9}, pages = {2140--2156}, publisher = {Elsevier}, title = {{Antibodies and complement are key drivers of thrombosis}}, doi = {10.1016/j.immuni.2024.08.007}, volume = {57}, year = {2024}, } @inbook{13052, abstract = {Imaging of the immunological synapse (IS) between dendritic cells (DCs) and T cells in suspension is hampered by suboptimal alignment of cell-cell contacts along the vertical imaging plane. This requires optical sectioning that often results in unsatisfactory resolution in time and space. Here, we present a workflow where DCs and T cells are confined between a layer of glass and polydimethylsiloxane (PDMS) that orients the cells along one, horizontal imaging plane, allowing for fast en-face-imaging of the DC-T cell IS.}, author = {Leithner, Alexander F and Merrin, Jack and Sixt, Michael K}, booktitle = {The Immune Synapse}, editor = {Baldari, Cosima and Dustin, Michael}, isbn = {9781071631348}, issn = {1940-6029}, pages = {137--147}, publisher = {Springer Nature}, title = {{En-Face Imaging of T Cell-Dendritic Cell Immunological Synapses}}, doi = {10.1007/978-1-0716-3135-5_9}, volume = {2654}, year = {2023}, } @article{14361, abstract = {Whether one considers swarming insects, flocking birds, or bacterial colonies, collective motion arises from the coordination of individuals and entails the adjustment of their respective velocities. In particular, in close confinements, such as those encountered by dense cell populations during development or regeneration, collective migration can only arise coordinately. Yet, how individuals unify their velocities is often not understood. Focusing on a finite number of cells in circular confinements, we identify waves of polymerizing actin that function as a pacemaker governing the speed of individual cells. We show that the onset of collective motion coincides with the synchronization of the wave nucleation frequencies across the population. Employing a simpler and more readily accessible mechanical model system of active spheres, we identify the synchronization of the individuals’ internal oscillators as one of the essential requirements to reach the corresponding collective state. The mechanical ‘toy’ experiment illustrates that the global synchronous state is achieved by nearest neighbor coupling. We suggest by analogy that local coupling and the synchronization of actin waves are essential for the emergent, self-organized motion of cell collectives.}, author = {Riedl, Michael and Mayer, Isabelle D and Merrin, Jack and Sixt, Michael K and Hof, Björn}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Synchronization in collectively moving inanimate and living active matter}}, doi = {10.1038/s41467-023-41432-1}, volume = {14}, year = {2023}, } @phdthesis{14530, abstract = {Most motions of many-body systems at any scale in nature with sufficient degrees of freedom tend to be chaotic; reaching from the orbital motion of planets, the air currents in our atmosphere, down to the water flowing through our pipelines or the movement of a population of bacteria. To the observer it is therefore intriguing when a moving collective exhibits order. Collective motion of flocks of birds, schools of fish or swarms of self-propelled particles or robots have been studied extensively over the past decades but the mechanisms involved in the transition from chaos to order remain unclear. Here, the interactions, that in most systems give rise to chaos, sustain order. In this thesis we investigate mechanisms that preserve, destabilize or lead to the ordered state. We show that endothelial cells migrating in circular confinements transition to a collective rotating state and concomitantly synchronize the frequencies of nucleating actin waves within individual cells. Consequently, the frequency dependent cell migration speed uniformizes across the population. Complementary to the WAVE dependent nucleation of traveling actin waves, we show that in leukocytes the actin polymerization depending on WASp generates pushing forces locally at stationary patches. Next, in pipe flows, we study methods to disrupt the self--sustaining cycle of turbulence and therefore relaminarize the flow. While we find in pulsating flow conditions that turbulence emerges through a helical instability during the decelerating phase. Finally, we show quantitatively in brain slices of mice that wild-type control neurons can compensate the migratory deficits of a genetically modified neuronal sub--population in the developing cortex. }, author = {Riedl, Michael}, issn = {2663-337X}, keywords = {Synchronization, Collective Movement, Active Matter, Cell Migration, Active Colloids}, pages = {260}, publisher = {Institute of Science and Technology Austria}, title = {{Synchronization in collectively moving active matter}}, doi = {10.15479/14530}, year = {2023}, } @article{14555, abstract = {The intricate regulatory processes behind actin polymerization play a crucial role in cellular biology, including essential mechanisms such as cell migration or cell division. However, the self-organizing principles governing actin polymerization are still poorly understood. In this perspective article, we compare the Belousov-Zhabotinsky (BZ) reaction, a classic and well understood chemical oscillator known for its self-organizing spatiotemporal dynamics, with the excitable dynamics of polymerizing actin. While the BZ reaction originates from the domain of inorganic chemistry, it shares remarkable similarities with actin polymerization, including the characteristic propagating waves, which are influenced by geometry and external fields, and the emergent collective behavior. Starting with a general description of emerging patterns, we elaborate on single droplets or cell-level dynamics, the influence of geometric confinements and conclude with collective interactions. Comparing these two systems sheds light on the universal nature of self-organization principles in both living and inanimate systems.}, author = {Riedl, Michael and Sixt, Michael K}, issn = {2296-634X}, journal = {Frontiers in Cell and Developmental Biology}, publisher = {Frontiers}, title = {{The excitable nature of polymerizing actin and the Belousov-Zhabotinsky reaction}}, doi = {10.3389/fcell.2023.1287420}, volume = {11}, year = {2023}, } @inbook{14848, abstract = {Regulating protein states is considered the core function of chaperones. However, despite their importance to all major cellular processes, the conformational changes that chaperones impart on polypeptide chains are difficult to study directly due to their heterogeneous, dynamic, and multi-step nature. Here, we review recent advances towards this aim using single-molecule manipulation methods, which are rapidly revealing new mechanisms of conformational control and helping to define a different perspective on the chaperone function.}, author = {Wruck, F. and Avellaneda Sarrió, Mario and Naqvi, M. M. and Koers, E. J. and Till, K. and Gross, L. and Moayed, F. and Roland, A. and Heling, L. W. H. J. and Mashaghi, A. and Tans, S. J.}, booktitle = {Biophysics of Molecular Chaperones}, editor = {Hiller, Sebastian and Liu, Maili and He, Lichun}, isbn = {9781839162824}, pages = {278--318}, publisher = {Royal Society of Chemistry}, title = {{Probing Single Chaperone Substrates}}, doi = {10.1039/bk9781839165986-00278}, volume = {29}, year = {2023}, } @phdthesis{14697, abstract = {During my Ph.D. research, I managed a series of projects, each focused on the mechanisms underlying cell migration. My work involved an in-depth examination of the complex strategies employed by neutrophils, with a specific focus on their ability to synchronize spatial-temporal cues and optimize their gradient perception. However, it is essential to acknowledge that not all projects yielded successful results, as some ideas were discontinued and are archived for future reference within this thesis. My main project investigated how neutrophils decode spatial cues for precise navigation. Human neutrophils showcased distinct movement patterns based on source type – linear or point-like. By combining single-cell tracking in 3D environments with proxy dyes, this project linked cell behaviors to gradient changes, revealing a stronger response to semi-exponential gradients from point sources. In addition, neutrophils exhibited oscillating migration speeds, using speed minima to adjust trajectories toward sources. Experiencing continuous concentration changes, they accelerated over time and employed a "Run and Fumble" strategy, alternating between consistent runs and strategic "tumbles" for efficient navigation. The project extended to the possibility of cells amplifying perceived gradients by enclosing their immediate surroundings, pushing attractants forward for enrichment while depleting it at the cell rear. Microfluidic devices were employed, and various experimental parameters configurations were optimized. Although significant differences in migratory efficacy were detected across pore sizes and device heights, quantifying gradient manipulation effects proved challenging. The "Laser-Assisted Protein Adsorption by Photobleaching" (LAPAP) project was promising, as it allowed the printing of gradients. Initially successful with dendritic cells, we aimed to adapt it for neutrophils. Through extensive experimentation with multiple parameters, we attempted to trigger responses from neutrophils. Despite these efforts and collaboration, the project failed due to practical challenges and limitations. Facing a lack of neutrophil-like cells at IST, we initially established the SCF-HoxB8 primary murine cell line. Despite their existence, their migratory behavior was largely unexplored due to potential limitations. Through differentiation protocol refinements we enhanced their migratory capabilities, though their capacity still lagged behind human neutrophils. Despite this, the improved migration potential of these cells pointed toward their utility for in vitro murine neutrophil migration studies.}, author = {Stopp, Julian A}, isbn = {978-3-99078-038-1}, issn = {2663-337X}, pages = {226}, publisher = {Institute of Science and Technology Austria}, title = {{Neutrophils on the hunt : Migratory strategies employed by neutrophils to fulfill their effector function}}, doi = {10.15479/at:ista:14697}, year = {2023}, } @article{14360, abstract = {To navigate through diverse tissues, migrating cells must balance persistent self-propelled motion with adaptive behaviors to circumvent obstacles. We identify a curvature-sensing mechanism underlying obstacle evasion in immune-like cells. Specifically, we propose that actin polymerization at the advancing edge of migrating cells is inhibited by the curvature-sensitive BAR domain protein Snx33 in regions with inward plasma membrane curvature. The genetic perturbation of this machinery reduces the cells’ capacity to evade obstructions combined with faster and more persistent cell migration in obstacle-free environments. Our results show how cells can read out their surface topography and utilize actin and plasma membrane biophysics to interpret their environment, allowing them to adaptively decide if they should move ahead or turn away. On the basis of our findings, we propose that the natural diversity of BAR domain proteins may allow cells to tune their curvature sensing machinery to match the shape characteristics in their environment.}, author = {Sitarska, Ewa and Almeida, Silvia Dias and Beckwith, Marianne Sandvold and Stopp, Julian A and Czuchnowski, Jakub and Siggel, Marc and Roessner, Rita and Tschanz, Aline and Ejsing, Christer and Schwab, Yannick and Kosinski, Jan and Sixt, Michael K and Kreshuk, Anna and Erzberger, Anna and Diz-Muñoz, Alba}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles}}, doi = {10.1038/s41467-023-41173-1}, volume = {14}, year = {2023}, } @article{14274, abstract = {Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with theory on leukocyte chemotaxis guided by the G protein–coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and a modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.}, author = {Alanko, Jonna H and Ucar, Mehmet C and Canigova, Nikola and Stopp, Julian A and Schwarz, Jan and Merrin, Jack and Hannezo, Edouard B and Sixt, Michael K}, issn = {2470-9468}, journal = {Science Immunology}, keywords = {General Medicine, Immunology}, number = {87}, publisher = {American Association for the Advancement of Science}, title = {{CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration}}, doi = {10.1126/sciimmunol.adc9584}, volume = {8}, year = {2023}, } @article{11588, abstract = {Visualizing cell behavior and effector function on a single cell level has been crucial for understanding key aspects of mammalian biology. Due to their small size, large number and rapid recruitment into thrombi, there is a lack of data on fate and behavior of individual platelets in thrombosis and hemostasis. Here we report the use of platelet lineage restricted multi-color reporter mouse strains to delineate platelet function on a single cell level. We show that genetic labeling allows for single platelet and megakaryocyte (MK) tracking and morphological analysis in vivo and in vitro, while not affecting lineage functions. Using Cre-driven Confetti expression, we provide insights into temporal gene expression patterns as well as spatial clustering of MK in the bone marrow. In the vasculature, shape analysis of activated platelets recruited to thrombi identifies ubiquitous filopodia formation with no evidence of lamellipodia formation. Single cell tracking in complex thrombi reveals prominent myosin-dependent motility of platelets and highlights thrombus formation as a highly dynamic process amenable to modification and intervention of the acto-myosin cytoskeleton. Platelet function assays combining flow cytrometry, as well as in vivo, ex vivo and in vitro imaging show unaltered platelet functions of multicolor reporter mice compared to wild-type controls. In conclusion, platelet lineage multicolor reporter mice prove useful in furthering our understanding of platelet and MK biology on a single cell level.}, author = {Nicolai, Leo and Kaiser, Rainer and Escaig, Raphael and Hoffknecht, Marie Louise and Anjum, Afra and Leunig, Alexander and Pircher, Joachim and Ehrlich, Andreas and Lorenz, Michael and Ishikawa-Ankerhold, Hellen and Aird, William C. and Massberg, Steffen and Gärtner, Florian R}, issn = {1592-8721}, journal = {Haematologica}, number = {7}, pages = {1669--1680}, publisher = {Ferrata Storti Foundation}, title = {{Single platelet and megakaryocyte morpho-dynamics uncovered by multicolor reporter mouse strains in vitro and in vivo}}, doi = {10.3324/haematol.2021.278896}, volume = {107}, year = {2022}, } @article{11843, abstract = {A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on mouse dendritic cells (DCs) as a binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of the pathogenic strain CFT073 to CD14 reduced DC migration by overactivation of integrins and blunted expression of co-stimulatory molecules by overactivating the NFAT (nuclear factor of activated T-cells) pathway, both rate-limiting factors of T cell activation. This response was binary at the single-cell level, but averaged in larger populations exposed to both piliated and non-piliated pathogens, presumably via the exchange of immunomodulatory cytokines. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease.}, author = {Tomasek, Kathrin and Leithner, Alexander F and Glatzová, Ivana and Lukesch, Michael S. and Guet, Calin C and Sixt, Michael K}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14}}, doi = {10.7554/eLife.78995}, volume = {11}, year = {2022}, } @article{12085, abstract = {Molecular catch bonds are ubiquitous in biology and essential for processes like leucocyte extravasion1 and cellular mechanosensing2. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this feature provides ‘strength on demand3’, thus enabling cells to increase rigidity under stress1,4,5,6. However, catch bonds are often weaker than slip bonds because they have cryptic binding sites that are usually buried7,8. Here we show that catch bonds render reconstituted cytoskeletal actin networks stronger than slip bonds, even though the individual bonds are weaker. Simulations show that slip bonds remain trapped in stress-free areas, whereas weak binding allows catch bonds to mitigate crack initiation by moving to high-tension areas. This ‘dissociation on demand’ explains how cells combine mechanical strength with the adaptability required for shape change, and is relevant to diseases where catch bonding is compromised7,9, including focal segmental glomerulosclerosis10 caused by the α-actinin-4 mutant studied here. We surmise that catch bonds are the key to create life-like materials.}, author = {Mulla, Yuval and Avellaneda Sarrió, Mario and Roland, Antoine and Baldauf, Lucia and Jung, Wonyeong and Kim, Taeyoon and Tans, Sander J. and Koenderink, Gijsje H.}, issn = {1476-4660}, journal = {Nature Materials}, number = {9}, pages = {1019--1023}, publisher = {Springer Nature}, title = {{Weak catch bonds make strong networks}}, doi = {10.1038/s41563-022-01288-0}, volume = {21}, year = {2022}, } @article{12119, abstract = {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.}, author = {Petzold, Tobias and Zhang, Zhe and Ballesteros, Iván and Saleh, Inas and Polzin, Amin and Thienel, Manuela and Liu, Lulu and Ul Ain, Qurrat and Ehreiser, Vincent and Weber, Christian and Kilani, Badr and Mertsch, Pontus and Götschke, Jeremias and Cremer, Sophie and Fu, Wenwen and Lorenz, Michael and Ishikawa-Ankerhold, Hellen and Raatz, Elisabeth and El-Nemr, Shaza and Görlach, Agnes and Marhuenda, Esther and Stark, Konstantin and Pircher, Joachim and Stegner, David and Gieger, Christian and Schmidt-Supprian, Marc and Gärtner, Florian R and Almendros, Isaac and Kelm, Malte and Schulz, Christian and Hidalgo, Andrés and Massberg, Steffen}, issn = {1074-7613}, journal = {Immunity}, keywords = {Infectious Diseases, Immunology, Immunology and Allergy}, number = {12}, pages = {2285--2299.e7}, publisher = {Elsevier}, title = {{Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease}}, doi = {10.1016/j.immuni.2022.10.001}, volume = {55}, year = {2022}, } @article{12133, abstract = {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.}, author = {Cremer, Sylvia and Sixt, Michael K}, issn = {1474-1741}, journal = {Nature Reviews Immunology}, keywords = {Energy Engineering and Power Technology, Fuel Technology}, number = {12}, pages = {713--714}, publisher = {Springer Nature}, title = {{Principles of disease defence in organisms, superorganisms and societies}}, doi = {10.1038/s41577-022-00797-y}, volume = {22}, year = {2022}, } @article{17072, abstract = {The collapse of polypeptides is thought important to protein folding, aggregation, intrinsic disorder, and phase separation. However, whether polypeptide collapse is modulated in cells to control protein states is unclear. Here, using integrated protein manipulation and imaging, we show that the chaperonin GroEL-ES can accelerate the folding of proteins by strengthening their collapse. GroEL induces contractile forces in substrate chains, which draws them into the cavity and triggers a general compaction and discrete folding transitions, even for slow-folding proteins. This collapse enhancement is strongest in the nucleotide-bound states of GroEL and is aided by GroES binding to the cavity rim and by the amphiphilic C-terminal tails at the cavity bottom. Collapse modulation is distinct from other proposed GroEL-ES folding acceleration mechanisms, including steric confinement and misfold unfolding. Given the prevalence of collapse throughout the proteome, we conjecture that collapse modulation is more generally relevant within the protein quality control machinery.}, author = {Naqvi, Mohsin M. and Avellaneda Sarrió, Mario and Roth, Andrew and Koers, Eline J. and Roland, Antoine and Sunderlikova, Vanda and Kramer, Günter and Rye, Hays S. and Tans, Sander J.}, issn = {2375-2548}, journal = {Science Advances}, number = {9}, publisher = {American Association for the Advancement of Science}, title = {{Protein chain collapse modulation and folding stimulation by GroEL-ES}}, doi = {10.1126/sciadv.abl6293}, volume = {8}, year = {2022}, } @article{9794, abstract = {Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.}, author = {Assen, Frank P and Abe, Jun and Hons, Miroslav and Hauschild, Robert and Shamipour, Shayan and Kaufmann, Walter and Costanzo, Tommaso and Krens, Gabriel and Brown, Markus and Ludewig, Burkhard and Hippenmeyer, Simon and Heisenberg, Carl-Philipp J and Weninger, Wolfgang and Hannezo, Edouard B and Luther, Sanjiv A. and Stein, Jens V. and Sixt, Michael K}, issn = {1529-2916}, journal = {Nature Immunology}, pages = {1246--1255}, publisher = {Springer Nature}, title = {{Multitier mechanics control stromal adaptations in swelling lymph nodes}}, doi = {10.1038/s41590-022-01257-4}, volume = {23}, year = {2022}, }