Medizinische Klinik und Poliklinik I
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  2. Medizinische Klinik und Poliklinik I
  3. Forschung und Lehre
  4. Grundlagenforschung
  5. AG Nicolai

AG Nicolai

  • Vascular Immunobiology

    The vascular system is not only a crucial interface between tissues in health and disease, but also the main battleground in humankind’s deadliest diseases, ranging from infection and sepsis to atherosclerosis and thrombosis. It is therefore crucial to understand the complex mechanisms involved in maintaining a healthy vasculature, as well as the pathophysiology of vascular injury, inflammation, and occlusion. Interestingly, most disease states in the circulatory system are mediated by the host immune system. We and others have identified an additional player in vascular immunology: platelets. These first responders shape innate and adaptive immune responses in acute and chronic inflammation and might offer new therapeutic avenues. For example, we were able to show that platelets use haptotactic migratory behavior for immunosurveillance in inflamed microvessels. Also, platelets team up with monocytes and neutrophils to form intravascular thrombi to entrap invading bacteria, a process termed immunothrombosis, which can also have detrimental effects for the host. To explore these complex mechanisms of vascular health and disease, we use state-of-the art mouse models, intravital imaging, in vitro functional assays and combine them with translational approaches.

    LMU Klinikum

    Ongoing projects

    Role of procoagulant platelet activity in health and disease (joint project with AG Kaiser)

    Platelets have a range of effector functions to fulfill their tasks in the vasculature. One of them is procoagulant activity – the exposure of phosphatidylserine on their surface that can then serve as a platform for activation of the coagulation cascade. The exact role of this process in vivo is insufficiently understood. We have shown that it contributes to inflammatory hemostasis (Kaiser et al, Blood, 2022) but also propagates venous thrombosis (Kaiser et al, Blood, 2024). We are now investigating its role in inflammation and potential therapeutic targeting of its signaling components.

    In vivo dynamics of platelet aging and turnover

    Platelet behavior over their lifespan in vivo has remained unclear. Using in vitro and in vivo assays, we revealed that young, reticulated platelets show heightened responses in the setting of clot formation, with corresponding, increased responses to agonists, adhesion, and retractile function (Anjum et al, Blood, 2024). Unexpectedly, aged platelets lost their thrombotic proficiency, but were more prone to react to inflammatory challenge: compared to reticulated platelets, this cohort was more likely to form platelet leukocyte aggregates and showed increased adhesion to neutrophils in vitro. In vivo, this was reflected in increased pulmonary recruitment of aged platelets in an acute lung injury model. This could have critical implications for transfusion medicine, as we observed a similar switch in phenotype in aged platelet concentrates. We are continuing to investigate these translational aspects of our discovery.

    Translational aspects of immunothrombosis

    During the COVID-19 pandemic, it became evident that immunothrombosis is a critical component of disease propagation, severity and complications. We, among others, were able to show that the interplay of platelets, the coagulation cascade and innate immune cells causes microvascular and macrovascular thrombosis, and correlates with disease severity (Nicolai et al, Circulation, 2020; Nicolai et al, JTH, 2021; Kaiser et al, JCI Insight, 2021). Importantly, this can be extrapolated to other diseases including vascular disease. We are using patient sampling, state-of-the-art Omics technology and deep phenotyping (Pekayvaz, Losert, Knottenberg et al, Nature Medicine, 2024, Pekayvaz et al, Nature Communications, 2022) to understand this better in vascular disease pathologies.

    Development of safe and efficacious antithrombotic drugs

    The available anti-thrombotic drugs used in primary and secondary prevention as well as acute thrombosis are reasonably efficacious; however, they all carry a significant risk of bleeding. We are now using sophisticated in vivo approaches to better differentiate pathological thrombotic and protective hemostatic mechanisms and develop novel nanotherapeutics harnessing these insights. We are collaborating with the Sen Gupta lab (Case western University, Cleveland) and the Hayden lab (TU Munich) for nanoparticle development and fluid dynamics.

    Platelet effector functions in atherosclerosis

    It has long been known that platelets are key players in promoting atherosclerotic plaque development. However, it remains insufficiently explored how this could be targeted in vivo as classical anti-aggregatory drugs like P2Y12 inhibitors or Aspirin show limited efficacy. We are therefore investigating how platelet effector functions contribute to plaque phenotype, with a particular focus on plaque destabilization.

    Systemic regulation of platelet activation state

    Platelets are critical cellular effectors of haemostasis by forming clots to seal off vascular injury. To fulfil their duty of preventing blood loss, these cells are highly abundant in blood and have a specialized cellular machinery that allows them to rapidly bind, react and activate upon loss of vascular integrity. Importantly, though, platelets are also key players in inflammation as well as thrombotic complications of vascular disease, and circulating activated platelets are known to be associated with adverse outcomes, necessitating tight control of their activity. If there are counterregulatory mechanisms in place that influence systemic platelet activation state remains unclear. We are investigating underlying mechanisms using genetic mouse models and complex transfusion setups.