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1.
Adv Sci (Weinh) ; 8(24): e2102381, 2021 12.
Article in English | MEDLINE | ID: mdl-34713625

ABSTRACT

Trauma is the leading cause of death in individuals under 44 years of age. Thorax trauma (TxT) is strongly associated with trauma-related death, an unbalanced innate immune response, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction. It is shown that different in vivo traumata, such as TxT or an in vitro polytrauma cytokine cocktail trigger secretion of small extracellular nanovesicles (sEVs) from endothelial cells with pro-inflammatory cargo. These sEVs transfer transcripts for ICAM-1, VCAM-1, E-selectin, and cytokines to systemically activate the endothelium, facilitate neutrophil-endothelium interactions, and destabilize barrier integrity. Inhibition of sEV-release after TxT in mice ameliorates local as well as systemic inflammation, neutrophil infiltration, and distant organ damage in kidneys (acute kidney injury, AKI). Vice versa, injection of TxT-plasma-sEVs into healthy animals is sufficient to trigger pulmonary and systemic inflammation as well as AKI. Accordingly, increased sEV concentrations and transfer of similar cargos are observed in polytrauma patients, suggesting a fundamental pathophysiological mechanism.


Subject(s)
Endothelial Cells/immunology , Extracellular Vesicles/immunology , Inflammation/immunology , Inflammation/physiopathology , Multiple Trauma/complications , Acute Kidney Injury/etiology , Acute Kidney Injury/immunology , Acute Kidney Injury/physiopathology , Animals , Disease Models, Animal , Endothelial Cells/physiology , Extracellular Vesicles/physiology , Male , Mice , Mice, Inbred C57BL , Multiple Trauma/immunology , Neutrophil Infiltration/physiology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/physiopathology , Sepsis/etiology , Sepsis/immunology , Sepsis/physiopathology
2.
J Cell Sci ; 132(24)2019 12 13.
Article in English | MEDLINE | ID: mdl-31727638

ABSTRACT

Constitutive secretion from the trans-Golgi-network (TGN) is facilitated by a concerted regulation of vesicle biogenesis and fission processes. The protein kinase D family (PKD) has been previously described to enhance vesicle fission by modifying the lipid environment. PKD also phosphorylates the actin regulatory protein cortactin at S298 to impair synergistic actin polymerization. We here report additional functions for PKD2 (also known as PRKD2) and cortactin in the regulation of actin polymerization during the fission of transport carriers from the TGN. Phosphorylation of cortactin at S298 impairs the interaction between WIP (also known as WIPF1) and cortactin. WIP stabilizes the autoinhibited conformation of N-WASP (also known as WASL). This leads to an inhibition of synergistic Arp2/3-complex-dependent actin polymerization at the TGN. PKD2 activity at the TGN is controlled by active CDC42-GTP which directly activates N-WASP, inhibits PKD2 and shifts the balance to non-S298-phosphorylated cortactin, which can in turn sequester WIP from N-WASP. Consequently, synergistic actin polymerization at the TGN and constitutive secretion are enhanced.


Subject(s)
Cortactin/metabolism , TRPP Cation Channels/metabolism , Actins , Animals , Blotting, Western , Fluorescence Resonance Energy Transfer , HEK293 Cells , HeLa Cells , Humans , Immunoprecipitation , MCF-7 Cells , Mice , NIH 3T3 Cells , Polymerization , Pyrazoles/pharmacology , Sulfonamides/pharmacology , cdc42 GTP-Binding Protein/antagonists & inhibitors , cdc42 GTP-Binding Protein/metabolism , trans-Golgi Network/genetics
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