The lipid crosstalk in thrombo-inflammation

The intricate interplay between platelets, polymorphonuclear neutrophils (PMNs), and the consequential Neutrophil Extracellular Trap formation (NETosis) is a major driver of thrombo- inflammatory diseases, significantly impacting the outcome after ischemia/reperfusion injury. Secreted bioactive lipids form the signaling lipidome network and are well-established mediators of cellular function. However, despite our recent work revealing a wide variety of lipid classes secreted upon platelet activation, the specifics of cell-specific quantitative signaling lipidome networks, cellular lipidome dynamics, and their impact on thrombo-inflammation remain largely unexplored. Our project aims to fill this crucial knowledge gap, understanding the complex lipid signaling in the development and progression of thrombo-inflammation. We will focus on the characterization of the platelet- and PMN-specific signaling lipidomes, the dynamics and chemical modifications of corresponding lipids in thrombosis/disease models, and finally, investigate the impact of promising bioactive lipids in human thrombo-inflammatory disorders, potentially leading to significant advancements in human health. The underlying project focuses on characterizing platelet- and PMN-specific signaling lipidome networks and lipid modifications during thrombosis. Consequently, we hypothesize that the lipid crosstalk between platelets and PMNs modulates the development and progression of inflammatory thrombus formation. The following key aims will be the object of our research: i) Delineation of the bioactive lipid landscape in platelets and PMNs. Assessment of lipid alterations in the absence or presence of stimuli. ii) Ilucidation of lipid-mediated crosstalk initiated by the identified secreted cell- specific bioactive lipids. Definition of their impact on NETosis, platelet activation, and thrombus formation. iii) Determination of signaling lipid dynamics and lipid tracking across cellular boundaries. Investigation of the impact of lipid modifications on the functional relevance of bioactive lipids. iv) Combination of the gained secretome data with functional and in vivo data to prove their physiological relevance. To meet these research aims, we will rely on recently established lipidomics and computational workflows, a plurality of functional in vitro assays, microscopy techniques, and transgenic mouse models. In a field where the crosstalk of platelet- and PMN-specific signaling lipidomes has been largely overlooked, our research brings a fresh perspective. We introduce a crucial element for the detailed chemical characterization of this crosstalk, which is a truly innovative approach. Our long-term goal is to provide a comprehensive map of the lipid signaling landscape during thrombo-inflammatory processes, identifying underlying lipid-modulating mechanisms and outcomes that could revolutionize prevention and treatment regimens for thrombo-inflammatory disorders in humans.