419 results on '"Preissner, KT"'
Search Results
2. P726Coronary NET burden and DNase activity in ST-elevation acute coronary syndrome are predictors of infarct size
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Mangold, A, Scherz, T, Alias, S, Hofbauer, T, Jakowitsch, J, Bangert, C, Pfaffenberger, S, Winter, MP, Preissner, KT, and Lang, IM
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- 2014
- Full Text
- View/download PDF
3. P166Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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- 2014
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4. 29 SIGLEC-1 (CD169) on monocytes/macrophages: a new receptor for extracellular self-RNA in triggering inflammatory responses via the sheddase TACE/ADAM17
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Cabrera-Fuentes, HA, primary, Preissner, KT, additional, and Boisvert, WA, additional
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- 2015
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5. Coagulation factor XII mediates fibrotic response to lung injury
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Wygrecka, M, primary, Jablonska, E, additional, Henneke, I, additional, Renne, T, additional, Panousis, K, additional, McKenzie, B, additional, Kosanovic, D, additional, Kwapiszewska, G, additional, Nolte, MW, additional, Schermuly, RT, additional, Preissner, KT, additional, and Markart, P, additional
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- 2015
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6. International registry for idiopathic pulmonary fibrosis
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Guenther, A, Eickelberg, O, Preissner, Kt, Chambers, R, Laurent, G, Wells, A, Crestani, B, Vancheri, Carlo, Bonniaud, P, Camus, P, Schmitz, G, Klepetko, W, Schultze, J, Vossmeyer, D, and Stumpf, P.
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- 2008
7. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane stem cell factor (SCF) and PAR-2/PKCalpha/Raf-1/p44/42 signaling pathway
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Wygrecka, M, primary, Dahal, B, additional, Kosanovic, D, additional, Petersen, F, additional, Taborski, B, additional, Preissner, KT, additional, Schermuly, RT, additional, and Markart, P, additional
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- 2013
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8. Protease-activated receptors 1 and 3 drive epithelial-mesenchymal transition in pulmonary fibrosis
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Wygrecka, M, primary, Berscheid, S, additional, Piskulak, K, additional, Didiasova, M, additional, Taborski, B, additional, Kwapiszewska, B, additional, Preissner, KT, additional, and Markart, P, additional
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- 2013
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9. Die Rolle von extrazellulärer RNA in der Angiogenese im Mausmodell
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Lin, J, primary, Schwarz, V, additional, Sharifpanah, F, additional, Jayarathne, SWG, additional, Hammes, HP, additional, Sauer, H, additional, and Preissner, KT, additional
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- 2012
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10. PAR-2 depletion protects against development of pulmonary hypertension
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Kwapiszewska, G, primary, Markart, P, additional, Marsh, LM, additional, Dahal, B, additional, Schermuly, RT, additional, Taube, C, additional, Meinhardt, A, additional, Ghofrani, HA, additional, Steinhoff, M, additional, Seeger, W, additional, Preissner, KT, additional, Weißmann, N, additional, and Wygrecka, M, additional
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- 2012
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11. Identifizierung und Charakterisierung von möglichen Biomarkern bei der Idiopathischen Pulmonalen Fibrose (IPF) mittels komparativer Proteomanalyse
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Korfei, M, primary, Schmitt, S, additional, Ruppert, C, additional, Henneke, I, additional, Markart, P, additional, Mahavadi, P, additional, Klepetko, W, additional, Fink, L, additional, Preissner, KT, additional, Schäfer, L, additional, Seeger, W, additional, and Günther, A, additional
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- 2010
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12. Potential Role of Protease-Activated Receptor-2 in Pathogenesis of Pulmonary Hypertension.
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Kwapiszewska, G, primary, Marsh, LM, additional, Markart, P, additional, Schermuly, RT, additional, Fink, L, additional, Seeger, W, additional, Preissner, KT, additional, Weissmann, N, additional, and Wygrecka, M, additional
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- 2009
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13. Role of surface displayed pneumococcal enolase in plasmin-mediated degradation of extracellular matrix and transmigration
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Bergmann, S, primary, Rohde, M, additional, Preissner, KT, additional, and Hammerschmidt, S, additional
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- 2006
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14. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization
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Brownlee, M, primary, Jonczyk, A, additional, Sutter, A, additional, Preissner, KT, additional, and Hammes, H-P, additional
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- 1996
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15. Interaction of single-chain urokinase with its receptor induces the appearance and disappearance of binding epitopes within the resultant complex for other cell surface proteins
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Higazi, AA, primary, Upson, RH, additional, Cohen, RL, additional, Manuppello, J, additional, Bognacki, J, additional, Henkin, J, additional, McCrae, KR, additional, Kounnas, MZ, additional, Strickland, DK, additional, Preissner, KT, additional, Lawler, J, additional, and Cines, DB, additional
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- 1996
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16. Clustering of vitronectin and RGD peptides on microspheres leads to engagement of integrins on the luminal aspect of endothelial cell membrane
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Zanetti, A, primary, Conforti, G, additional, Hess, S, additional, Martin-Padura, I, additional, Ghibaudi, E, additional, Preissner, KT, additional, and Dejana, E, additional
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- 1994
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17. Human megakaryocytes express clusterin and package it without apolipoprotein A-1 into alpha-granules
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Tschopp, J, primary, Jenne, DE, additional, Hertig, S, additional, Preissner, KT, additional, Morgenstern, H, additional, Sapino, AP, additional, and French, L, additional
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- 1993
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18. Inhibition of gelatinase B (matrix metalloprotease-9) activity reduces cellular inflammation and restores function of transplanted pancreatic islets.
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Lingwal N, Padmasekar M, Samikannu B, Bretzel RG, Preissner KT, Linn T, Lingwal, Neelam, Padmasekar, Manju, Samikannu, Balaji, Bretzel, Reinhard G, Preissner, Klaus T, and Linn, Thomas
- Abstract
Islet transplantation provides an approach to compensate for loss of insulin-producing cells in patients with type 1 diabetes. However, the intraportal route of transplantation is associated with instant inflammatory reactions to the graft and subsequent islet destruction as well. Although matrix metalloprotease (MMP)-2 and -9 are involved in both remodeling of extracellular matrix and leukocyte migration, their influence on the outcome of islet transplantation has not been characterized. We observed comparable MMP-2 mRNA expressions in control and transplanted groups of mice, whereas MMP-9 mRNA and protein expression levels increased after islet transplantation. Immunostaining for CD11b (Mac-1)-expressing leukocytes (macrophage, neutrophils) and Ly6G (neutrophils) revealed substantially reduced inflammatory cell migration into islet-transplanted liver in MMP-9 knockout recipients. Moreover, gelatinase inhibition resulted in a significant increase in the insulin content of transplanted pancreatic islets and reduced macrophage and neutrophil influx compared with the control group. These results indicate that the increase of MMP-9 expression and activity after islet transplantation is directly related to enhanced leukocyte migration and that early islet graft survival can be improved by inhibiting MMP-9 (gelatinase B) activity. [ABSTRACT FROM AUTHOR]
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- 2012
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19. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury.
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Grommes J, Alard JE, Drechsler M, Wantha S, Mörgelin M, Kuebler WM, Jacobs M, von Hundelshausen P, Markart P, Wygrecka M, Preissner KT, Hackeng TM, Koenen RR, Weber C, Soehnlein O, Grommes, Jochen, Alard, Jean-Eric, Drechsler, Maik, Wantha, Sarawuth, and Mörgelin, Matthias
- Abstract
Rationale: Acute lung injury (ALI) causes high mortality, but its molecular mechanisms and therapeutic options remain ill-defined. Gram-negative bacterial infections are the main cause of ALI, leading to lung neutrophil infiltration, permeability increases, deterioration of gas exchange, and lung damage. Platelets are activated during ALI, but insights into their mechanistic contribution to neutrophil accumulation in the lung are elusive.Objectives: To determine mechanisms of platelet-mediated neutrophil recruitment in ALI.Methods: Interference with platelet-neutrophil interactions using antagonists to P-selectin and glycoprotein IIb/IIIa or a small peptide antagonist disrupting platelet chemokine heteromer formation in mouse models of ALI.Measurements and Main Results: In a murine model of LPS-induced ALI, we uncover important roles for neutrophils and platelets in permeability changes and subsequent lung damage. Furthermore, platelet depletion abrogated lung neutrophil infiltration, suggesting a sequential participation of platelets and neutrophils. Whereas antagonists to P-selectin and glycoprotein IIb/IIIa had no effects on LPS-mediated ALI, antibodies to the platelet-derived chemokines CCL5 and CXCL4 strongly diminished neutrophil eflux and permeability changes. The two chemokines were found to form heteromers in human and murine ALI samples, positively correlating with leukocyte influx into the lung. Disruption of CCL5-CXCL4 heteromers in LPS-, acid-, and sepsis-induced ALI abolished lung edema, neutrophil infiltration, and tissue damage, thereby revealing a causal contribution.Conclusions: Taken together, our data identify a novel function of platelet-derived chemokine heteromers during ALI and demonstrate means for therapeutic interference. [ABSTRACT FROM AUTHOR]- Published
- 2012
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20. Shedding of low-density lipoprotein receptor-related protein-1 in acute respiratory distress syndrome.
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Wygrecka M, Wilhelm J, Jablonska E, Zakrzewicz D, Preissner KT, Seeger W, Guenther A, and Markart P
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PROTEIN metabolism ,BODY fluids ,CELLS ,FIBROBLASTS ,LUNGS ,MEMBRANE proteins ,PROTEOLYTIC enzymes ,ADULT respiratory distress syndrome ,SEVERITY of illness index ,OSMOLAR concentration - Abstract
RATIONALE: Low-density lipoprotein receptor-related protein-1 (LRP-1) mediates the endocytic clearance of various proteinases, including matrix metalloproteinases (MMPs). The ectodomain of LRP-1 can be shed from the cell surface, releasing a soluble form of this receptor (sLRP-1), which antagonizes ligand endocytosis by cellular LRP-1. OBJECTIVES: To assess if increased LRP-1 shedding occurs in the lungs of patients with acute respiratory distress syndrome (ARDS) and may lead to the accumulation of MMPs and subsequent tissue injury. METHODS: We determined sLRP-1 levels in bronchoalveolar lavage fluids (BALF) from 46 patients with ARDS and their correlation with MMP concentration and disease severity. In complementary in vitro studies, we investigated the mechanisms underlying the LRP-1 release from the cell surface and its impact on MMP cellular uptake. MEASUREMENTS AND MAIN RESULTS: sLRP-1 levels were significantly elevated in BALF but not in plasma from patients with ARDS compared with control subjects and further increased in the later course of the disease. Baseline BALF sLRP-1 concentration was positively correlated with disease severity and significantly higher in nonsurvivors compared with survivors. The presence of ARDS BALF enhanced LRP-1 shedding from cultured lung fibroblasts but not from alveolar type II cells or macrophages. This process was blocked when ARDS BALF was supplemented with metalloproteinase inhibitor resulting in enhanced cellular uptake and degradation of MMP-2 and -9. Accordingly, sLRP-1 BALF concentration in patients with ARDS was positively correlated with MMP levels and laminin, a marker of basement membrane disruption. CONCLUSIONS: Increased LRP-1 shedding prevents the cellular clearance of MMPs and might thereby contribute to tissue destruction in ARDS lungs. [ABSTRACT FROM AUTHOR]
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- 2011
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21. Importance of phosphoinositide 3-kinase gamma in the host defense against pneumococcal infection.
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Maus UA, Backi M, Winter C, Srivastava M, Schwarz MK, Rückle T, Paton JC, Briles D, Mack M, Welte T, Maus R, Bohle RM, Seeger W, Rommel C, Hirsch E, Lohmeyer J, and Preissner KT
- Abstract
Rationale: The pivotal role of phosphoinositide 3-kinase gamma (PI3Kgamma) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3Kgamma signaling might increase the risk of bacterial infections in humans. Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3Kgamma would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae. Methods: PI3Kgamma knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined. Measurements and Main Results: PI3Kgamma KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae-infected PI3Kgamma KO mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia. Conclusions: PI3Kgamma gene deletion or pharmacologic inhibition of PI3Kgamma leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacologic inhibition of PI3Kgamma signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems. [ABSTRACT FROM AUTHOR]
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- 2007
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22. Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome.
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Blaes F, Fühlhuber V, Korfei M, Tschernatsch M, Behnisch W, Rostasy K, Hero B, Kaps M, and Preissner KT
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- 2005
23. The heparin binding domain of S-protein/vitronectin binds to complement components C7, C8, and C9 and perforin from cytolytic T-cells and inhibits their lytic activities
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Danièle Masson, J Tschopp, Peitsch M, Preissner Kt, and S Schäfer
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Pore Forming Cytotoxic Proteins ,Peptide ,Biology ,Binding, Competitive ,Hemolysis ,Biochemistry ,Chromatography, Affinity ,chemistry.chemical_compound ,Animals ,Vitronectin ,Binding site ,Glycoproteins ,chemistry.chemical_classification ,Glycosaminoglycan binding ,Membrane Glycoproteins ,Sheep ,Heparin ,Perforin ,Immunochemistry ,Antibodies, Monoclonal ,Membrane Proteins ,Complement System Proteins ,Complement C9 ,Complement C8 ,Molecular biology ,Complement C7 ,chemistry ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Cyanogen bromide ,Peptides ,Complement membrane attack complex ,T-Lymphocytes, Cytotoxic ,Binding domain - Abstract
S-Protein/vitronectin is a serum glycoprotein that inhibits the lytic activity of the membrane attack complex of complement, i.e., of the complex including the proteins C5b, C6, C7, C8, and C9n. We show that intact S-protein/vitronectin or its cyanogen bromide generated fragments also inhibit the hemolysis mediated by perforin from cytotoxic T-cells at 45 and 11 microM, respectively. The glycosaminoglycan binding site of S-protein/vitronectin is responsible for the inhibition, since a synthetic peptide corresponding to a part of this highly basic domain (amino acid residues 348-360) inhibits complement- as well as perforin-mediated cytolysis. In the case of C9, the synthetic peptide binds to the acidic residues occurring in its N-terminal cysteine-rich domain (residues 101-111). Antibodies raised against this particular segment react 25-fold better with the polymerized form of C9 as compared with its monomeric form, indicating that this site becomes exposed only upon the hydrophilic-amphiphilic transition of C9. Since the cysteine-rich domain of C9 has been shown to be highly conserved in C6, C7, and C8 as well as in perforin, the inhibition of the lytic activities of these molecules by S-protein/vitronectin or by peptides corresponding to its heparin binding site may be explained by a similar mechanism.
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- 1988
24. Identification of and partial characterization of platelet vitronectin: evidence for complex formation with platelet-derived plasminogen activator inhibitor-1
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Preissner, KT, Holzhuter, S, Justus, C, and Muller-Berghaus, G
- Abstract
Vitronectin (VN; = complement S-protein), a plasma glycoprotein that is also associated with extracellular sites, was identified in washed human platelets contaminated with less than 0.05% of plasma VN. A specific enzyme-linked immunosorbent assay (ELISA) for VN has been developed and was used to detect and to quantitate VN in detergent extracts of washed platelets with 8.1 +/- 4.6 micrograms/10(9) platelets (n = 10), representing about 0.8% of the plasma VN pool. Platelet and plasma VN were similar by immunochemical criteria using Western-blot analysis, although platelet VN was mainly found as partially proteolyzed polypeptide. Total release of platelet VN occurred at optimal doses of Ca-ionophore 23187 or thrombin, whereas no VN was released by platelet treatment with digitonin or Staphylococcus alpha-toxin. During stimulation of washed platelets with various concentrations of thrombin, the nearly concomitant release of VN and plasminogen activator inhibitor-1 (PAI-1) together with platelet factor 4 indicated the association of VN with inner-platelet storage granules. Furthermore, platelet VN and PAI-1 in Ca-ionophore releasates comigrated during ultracentrifugation in high mol wt fractions of sucrose density gradients, indicating a possible association of both components. Complex formation of platelet VN and PAI-1 was verified by a sensitive enzyme-linked immunosorbent assay (ELISA) and accounts at least in part for a high molecular form of platelet VN. The identification of platelet VN and its binding to platelet PAI-1 raises the possibility that VN, in contrast to other adhesive proteins, may participate in localized regulatory functions of blood coagulation and fibrinolysis in platelet-matrix interactions and the protection of the matrix against proteolysis.
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- 1989
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25. Attachment of cultured human endothelial cells is promoted by specific association with S protein (vitronectin) as well as with the ternary S protein-thrombin-antithrombin III complex
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Preissner, KT, Anders, E, Grulich-Henn, J, and Muller-Berghaus, G
- Abstract
The interaction of the multifunctional S protein (vitronectin) with cultured human endothelial cells of macrovascular and microvascular origin was investigated. Purified S protein, coated on polystyrene Petri dishes, induced dose-dependent and time-dependent attachment and spreading of human umbilical vein endothelial cells (HUVECs) as well as human omental tissue microvascular endothelial cells (HOTMECs) at 37 degrees C. Not only isolated S protein, but also the ternary S protein- thrombin-antithrombin III (STAT) complex promoted attachment of approximately 90% of the cells within 2 hours at an S protein concentration of 0.13 mumol/L. Inhibition of attachment in these experiments was achieved by the addition of the cell-attachment pentapeptide Gly-Arg-Gly-Asp-Ser and by monospecific antibodies against S protein, whereas nonrelated peptides or antibodies against fibronectin, fibrinogen, or von Willebrand factor (vWF) were ineffective. Direct binding of S protein to HUVECs and HOTMECs was studied with cells in suspension at a density of 1 x 10(6) cells/mL and was maximal after 120 minutes. S protein bound to both cell types in a dose-dependent fashion with an estimated dissociation constant Kd = 0.2 mumol/L. At a 200-fold to 500-fold molar excess of unlabeled S protein, greater than 80% of bound radiolabeled S protein was displaceable, whereas binding was reduced to 30% to 50% by addition of the pentapeptide, the STAT complex, or by physiologic concentrations of fibrinogen or vWF as well as Fab fragments of anti(human S protein)IgG, but not by Fab rabbit IgG. These findings present evidence for the specific association of S protein with endothelial cells ultimately leading to attachment and spreading of cells. Moreover, a novel function for the ternary STAT complex, which induced endothelial cell attachment and spreading virtually identical to free S protein, is described. These data further suggest a possible role for S protein during coagulation as major vessel wall-related adhesive protein at sites of vascular injury.
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- 1988
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26. Differences in coagulant and fibrinolytic activities of cultured human endothelial cells derived from omental tissue microvessels and umbilical veins
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Speiser, W, Anders, E, Preissner, KT, Wagner, O, and Muller-Berghaus, G
- Abstract
Large vessel and microvascular endothelial cells were compared in their capacity to synthesize and secrete coagulant and fibrinolytic factors. Human omental tissue microvascular endothelial cells (HOTMEC) and human umbilical vein endothelial cells (HUVEC) were isolated, grown to confluency under identical conditions, and studied in primary cultures. After an incubation period of 12 hours in serum-free medium, the conditioned medium of confluent HOTMEC contained 100-fold higher levels of tissue plasminogen activator (tPA) antigen than that of HUVEC. The conditioned media as well as the lysates of both cell types did not contain any free tPA activity, but the free plasminogen activator inhibitor capacity was found intracellularly as well as extracellularly. Although von Willebrand factor was detected in both cell types by immunofluorescence, measurable amounts were only found in HUVEC using an enzyme-linked immunosorbent assay. The kinetics of protein C activation by thrombin on the surface of once-passaged cells were identical for HOTMEC and HUVEC. The present study indicates that cultivated HOTMEC produce larger quantities of tPA than HUVEC do, possess smaller amounts of von Willebrand factor than HUVEC do, and express thrombomodulin for protein C activation as effectively as HUVEC.
- Published
- 1987
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27. PURIFICATION AND CHARACTERIZATION OF A PLASMINOGEN-ACTIVATOR INHIBITOR-1 BINDING-PROTEIN FROM HUMAN-PLASMA - IDENTIFICATION AS A MULTIMERIC FORM OF S-PROTEIN (VITRONECTIN)
- Author
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Declerck, Pj, Demol, M., Marie-christine ALESSI, Baudner, S., Paques, Ep, Preissner, Kt, Mullerberghaus, G., and Collen, D.
28. P726 Coronary NET burden and DNase activity in ST-elevation acute coronary syndrome are predictors of infarct size.
- Author
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Mangold, A, Scherz, T, Alias, S, Hofbauer, T, Jakowitsch, J, Bangert, C, Pfaffenberger, S, Winter, MP, Preissner, KT, and Lang, IM
- Subjects
HEART disease diagnosis ,DNA ,CELL culture ,EXTRACELLULAR signal-regulated kinases ,GENE expression ,MYELOPEROXIDASE - Abstract
Background: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome (STE-ACS) are poorly understood. We have previously reported accumulation of neutrophils (polymorphonuclear cells [PMNs]) in culprit lesion site thrombi. The goal of the present study was to quantify PMNs, their formation of neutrophil extracellular traps (NETs), and to examine the relationships of extracellular DNA, DNase and clinical outcomes.Methods and Results: We analyzed coronary thrombectomy aspirates from 112 patients undergoing primary percutaneous coronary intervention. Compared to systemic PMNs, coronary thrombus PMNs were characterized by high expression of activation markers and by the formation of aggregates with platelets. Nucleosomes, neutrophil elastase, myeloperoxidase and myeloid-related protein 8/14 were increased in coronary plasma, and NETs significantly contributed to the scaffolds of particulate coronary thrombi. Thrombus NET burden was directly correlated with infarct size, while culprit site DNase activity showed a reverse correlation with infarct size. Recombinant DNase accelerated lysis of coronary thrombi ex vivo.Conclusion: PMNs are highly activated in STE-ACS and undergo NETosis at the culprit lesion site. Coronary NET burden and DNase activity are predictors of myocardial infarct size. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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29. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.
- Author
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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RNA ,REPERFUSION injury ,HEART failure ,RIBONUCLEASES ,MORTALITY ,MYOCARDIAL infarction - Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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30. P735 Regulation of macrophage polarization by extracellular RNA: The role of sialoadhesin-1.
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Cabrera-Fuentes, H A, Galuska, S, Meiler, S, Baumer, Y, Mccurdy, S, Fischer, S, Preissner, KT, and Boisvert, W
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MACROPHAGE activation ,EXTRACELLULAR matrix proteins ,RNA ,CELL adhesion ,TUMOR necrosis factors ,PHENOTYPES ,CYTOKINES - Abstract
Macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. This unique property of macrophages allows these cells to modulate chronic inflammatory processes such as atherogenesis. We have previously shown that extracellular RNA (eRNA) can exert prothrombotic and inflammatory properties in the vasculature as a cofactor in protease auto-activation and cytokine mobilization. Given the association of eRNA with macrophages within atherosclerotic lesions, we assessed whether eRNA generated by the macrophages themselves may induce inflammatory responses within macrophages, independent of Toll-like receptor signaling. Recombinant mouse macrophage CSF-driven bone marrow-derived macrophage (BMDM) differentiation was skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in the overexpression of inflammatory markers such as Tnf-α, Arg2, Il-1β, Il-6, or Ifn-Γ together with Il-12 and iNOS, whereas anti-inflammatory genes such as Il-10 and Il-4 together with Arg1 and macrophage mannose receptor-2 (Cd206) were significantly down-regulated by eRNA. Accordingly, the release of TNF-α and IL-6 proteins into the cell supernatant was significantly elevated by eRNA stimulation. Moreover, the capacity of granulocyte macrophage CSF-driven BMDM differentiation (already representing M1 phenotype) towards further M1 polarization in response to eRNA was moderate. Nevertheless, a significant down-regulation of M2 markers was found. Sialoadhesin-1 (SN-1) is a membrane-anchored basic protein, predominantly expressed on macrophages and involved in cellular interactions via recognition of sialylated glycoconjugates. Interestingly, exposure of SN-1-/- BMDM towards eRNA resulted in prominent down-regulation of pro-inflammatory cytokines together with M1 phenotype markers, while anti-inflammatory cytokines together with M2 phenotype mediators were significantly raised. In accordance with our proposal that eRNA serves as pro-inflammatory "alarm signal" during physiologically distressed conditions, these data may shed light on the role of eRNA and macrophages in chronic inflammatory environment such as atherosclerosis. The self-perpetuating process of atherosclerosis as a largely inflammation-driven pathology may be controlled by SN-1 expression on lesional macrophages as well as the injury-mediated release of eRNA as a master trigger in inflammation. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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31. Mutual regulation of CD4 + T cells and intravascular fibrin in infections.
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Mueller TT, Pilartz M, Thakur M, LangHeinrich T, Luo J, Block R, Hoeflinger JKL, Meister S, Karaj F, Perez LG, Öllinger R, Engleitner T, Thoss J, Voelkl M, Tersteeg C, Koedel U, Kohlmaier AZ, Teupser D, Wygrecka M, Ye H, Preissner KT, Radbruch H, Elezkurtaj S, Mack M, Von Hundelshausen P, Weber C, Massberg S, Schulz C, Rad R, Huber S, Ishikawa-Ankerhold H, and Engelmann B
- Subjects
- Humans, Animals, Infections immunology, Lymphocyte Activation immunology, Thrombosis etiology, Thrombosis immunology, Fibrin metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism
- Abstract
Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell-dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T-helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin-CD4+ T-cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T-cell activation, which is initially triggered by IL-12p40- and MHC-II-dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the thrombin-activatable fibrinolysis inhibitor (TAFI) with fibrin whereby fibrin deposition is increased by TAFI in the absence but not in the presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1-dependent T-helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.
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- 2024
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32. Treatment with RNase alleviates brain injury but not neuroinflammation in neonatal hypoxia/ischemia.
- Author
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Anderberg RH, Andersson EA, Bucher V, Preissner KT, Mallard C, and Ek CJ
- Subjects
- Animals, Infant, Newborn, Infant, Humans, Animals, Newborn, Ribonucleases metabolism, Ribonucleases pharmacology, Brain metabolism, Ischemia drug therapy, Disease Models, Animal, Brain Injuries drug therapy, Hypoxia-Ischemia, Brain, Neuroprotective Agents pharmacology
- Abstract
There is a need for new treatments to reduce brain injuries derived from neonatal hypoxia/ischemia. The only viable option used in the clinic today in infants born at term is therapeutic hypothermia, which has a limited efficacy. Treatments with exogenous RNase have shown great promise in a range of different adult animal models including stroke, ischemia/reperfusion injury, or experimental heart transplantation, often by conferring vascular protective and anti-inflammatory effects. However, any neuroprotective function of RNase treatment in the neonate remains unknown. Using a well-established model of neonatal hypoxic/ischemic brain injury, we evaluated the influence of RNase treatment on RNase activity, gray and white matter tissue loss, blood-brain barrier function, as well as levels and expression of inflammatory cytokines in the brain up to 6 h after the injury using multiplex immunoassay and RT-PCR. Intraperitoneal treatment with RNase increased RNase activity in both plasma and cerebropinal fluids. The RNase treatment resulted in a reduction of brain tissue loss but did not affect the blood-brain barrier function and had only a minor modulatory effect on the inflammatory response. It is concluded that RNase treatment may be promising as a neuroprotective regimen, whereas the mechanistic effects of this treatment appear to be different in the neonate compared to the adult and need further investigation., (© 2024 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)
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- 2024
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33. Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury neointimal hyperplasia.
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Crespo-Avilan GE, Hernandez-Resendiz S, Ramachandra CJ, Ungureanu V, Lin YH, Lu S, Bernhagen J, El Bounkari O, Preissner KT, Liehn EA, and Hausenloy DJ
- Subjects
- Humans, Mice, Animals, Hyperplasia pathology, Metabolic Reprogramming, Cell Movement, Muscle, Smooth, Vascular pathology, Neointima metabolism, Anti-Inflammatory Agents pharmacology, Disease Models, Animal, Cell Proliferation, Vascular System Injuries genetics, Quinazolinones
- Abstract
Background and Aims: New treatments are needed to prevent neointimal hyperplasia that contributes to post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) and peripheral arterial disease (PAD). We investigated whether modulating mitochondrial function using mitochondrial division inhibitor-1 (Mdivi-1) could reduce post-vascular injury neointimal hyperplasia by metabolic reprogramming of macrophages from a pro-inflammatory to anti-inflammatory phenotype., Methods and Results: In vivo Mdivi-1 treatment of Apoe
-/- mice fed a high-fat diet and subjected to carotid-wire injury decreased neointimal hyperplasia by 68%, reduced numbers of plaque vascular smooth muscle cells and pro-inflammatory M1-like macrophages, and decreased plaque inflammation, endothelial activation, and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from a pro-inflammatory M1-like to an anti-inflammatory M2-like phenotype, reduced monocyte chemotaxis and migration to CCL2 and macrophage colony stimulating factor (M-CSF) and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-type-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-like phenotype by inhibiting oxidative phosphorylation and attenuating the increase in succinate levels and correcting the decreased levels of arginine and citrulline., Conclusions: We report that treatment with Mdivi-1 inhibits post-vascular injury neointimal hyperplasia by metabolic reprogramming macrophages towards an anti-inflammatory phenotype thereby highlighting the therapeutic potential of Mdivi-1 for preventing neointimal hyperplasia and restenosis following angioplasty and stenting in CAD and PAD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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34. Treatment with Cobra Venom Factor Decreases Ischemic Tissue Damage in Mice.
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Azubuike-Osu SO, Kuhs A, Götz P, Faro A, Preissner KT, Arnholdt C, and Deindl E
- Abstract
Tissue ischemia, caused by the blockage of blood vessels, can result in substantial damage and impaired tissue performance. Information regarding the functional contribution of the complement system in the context of ischemia and angiogenesis is lacking. To investigate the influence of complement activation and depletion upon femoral artery ligation (FAL), Cobra venom factor (CVF) (that functionally resembles C3b, the activated form of complement component C3) was applied in mice in comparison to control mice. Seven days after induction of muscle ischemia through FAL, gastrocnemius muscles of mice were excised and subjected to (immuno-)histological analyses. H&E and apoptotic cell staining (TUNEL) staining revealed a significant reduction in ischemic tissue damage in CVF-treated mice compared to controls. The control mice, however, exhibited a significantly higher capillary-to-muscle fiber ratio and a higher number of proliferating endothelial cells (CD31
+ /CD45- /BrdU+ ). The total number of leukocytes (CD45+ ) substantially decreased in CVF-treated mice versus control mice. Moreover, the CVF-treated group displayed a shift towards the M2-like anti-inflammatory and regenerative macrophage phenotype (CD68+ /MRC1+ ). In conclusion, our findings suggest that treatment with CVF leads to reduced ischemic tissue damage along with decreased leukocyte recruitment but increased numbers of M2-like polarized macrophages, thereby enhancing tissue regeneration, repair, and healing.- Published
- 2024
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35. Correction for Niemann et al., "More Is Not Always Better-the Double-Headed Role of Fibronectin in Staphylococcus aureus Host Cell Invasion".
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Niemann S, Nguyen M-T, Eble JA, Chasan AI, Mrakovcic M, Preissner KT, Roßlenbroich S, Peters G, and Herrmann M
- Published
- 2023
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36. Remote ischemic preconditioning in patients undergoing cardiac surgery with six ischemic cycles.
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Böning A, Flicker L, Rodriguez-Montesinos J, Cabrera-Fuentes H, Preissner KT, Niemann B, and Taghiyev ZT
- Subjects
- Humans, Tumor Necrosis Factor-alpha metabolism, Ischemia, Myocardium metabolism, Ischemic Preconditioning, Cardiac Surgical Procedures
- Abstract
Background: We have previously shown that remote ischemic preconditioning (RIP), which utilizes in part the extracellular RNA (eRNA)/RNase1 pathway, can induce ischemic tolerance in humans. Because RIP has thus far been tested only with four cycles of extremity ischemia/reperfusion, we investigated the influence of six cycles of ischemia on the eRNA/RNase1 pathway in cardiac patients., Methods: Six cycles of RIP were carried out in 14 patients undergoing cardiac surgery. Blood samples were taken at 13 timepoints during surgery and at three timepoints after surgery for determining serum levels of RNase1, eRNA, and TNF-α. Trans-cardiac gradients between the myocardial blood inflow and outflow were calculated., Results: Between the fourth and the sixth RIP cycles, a noticeable increase in the levels of eRNA (fourth: 151.6 (SD: 44.2) ng/ml vs sixth: 181.8 (SD: 87.5) ng/ml, p = .071), and a significant increase in RNase1 (fourth: 151.1 (SD: 42.6) U/ml vs sixth: 175.3 (SD: 41.2) U/ml, p = .001), were noted. The trans-cardiac gradients of RNase1 and eRNA before and after ischemia were not significantly different ( p = .158 and p = .221; p = .397 and p = .683, respectively). Likewise, the trans-cardiac gradient of TNF-α was similar before and after ischemia. During the first 48 h after the surgery, RNase1 activity rose significantly and exceeded baseline values (135.7 (SD: 40.6) U/ml before and 279.2 (SD: 85.6) U/ml after surgery, p = .001) as did eRNA levels (148,6 (SD: 35.4) ng/ml before and 396.5 (SD: 154.5) ng/ml after surgery, p = .005), whereas TNF-α levels decreased significantly (91.7 (SD: 47.7) pg/ml before and 35.7 (SD: 36.9) pg/ml after surgery, p = .001)., Conclusion: Six RIP cycles increased the RNase1 levels significantly above those observed with four cycles. More clinical data are required to show whether this translates into a benefit for patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2023
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37. Calafiore cardioplegia offers better myocardial protection in adult and senescent rat hearts than Del Nido cardioplegia.
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Böning A, Menzebach S, Heep M, Gärtner U, Preissner KT, Niemann B, and Taghiyev ZT
- Abstract
Objectives: We compared the cardioprotective capacity of Del Nido cardioplegia and warm Calafiore blood cardioplegia in an experimental setting during 90 min of ischaemia., Methods: 20 adult and 20 senescent rat hearts were isolated and mounted on a blood-perfused, pressure-controlled Langendorff apparatus. After a stabilization period, cardiac arrest (90 min) was induced by the administration of either Calafiore (Cala) or Del Nido solution (DNS). While Cala was given warm and intermittently, DNS was given as a cold single shot. During 90 min of reperfusion, cardiac function and metabolism were evaluated and biomarker levels were measured. After the end of the experiment, hearts were prepared for electronmicroscopic investigation., Results: Hearts exposed to Cala recovered faster during reperfusion compared with hearts administered DNS (Cala vs DNS at 30 min reperfusion: left ventricular developed pressure 72, SD: 22% of baseline (BL) versus 40, SD: 32% of BL, p < .001, and positive derived left ventricular pressure over time was better in both adult and senescent Cala groups (96, SD: 31% of BL) than in the DNS groups (39, SD: 27% of BL, p < .001). Ischaemic contractures were seen in the DNS groups starting after 30 min of ischaemia, whereas no rise in diastolic pressure was observed for the Cala groups. Accordingly, lactate production was higher after DNS (1.23 mg/dl (SD 0.87) than after Cala (0.33 mg/dl (SD 0.68), p = .015) at the beginning of reperfusion. Troponin I levels at the end of reperfusion were higher after DNS treatment in adult hearts (DNS: 287.9 SD: 147.7 ng/mL vs Cala 91.2: SD: 94.7 ng/mL, p = .02) and in senescent hearts (DNS: 376.5 (SD: 162.8) ng/ml versus Cala 104.7 (SD: 150.2) ng/ml, p = .025). Electron microscopy showed that the cellular oedema index was higher in adult DNS hearts (1.2 ± 0.2) than in adult Cala hearts (0.8 ± 0.1, p = .012), whereas the VS ratio was similar (0.18 ± 0.01 vs 0.17 ± 0.03)., Conclusion: Calafiore cardioplegia offers better myocardial protection from ischaemia/reperfusion-related damage in isolated perfused adult and senescent rat hearts than Del Nido cardioplegia., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2023
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38. Brain alarm by self-extracellular nucleic acids: from neuroinflammation to neurodegeneration.
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Kunze R, Fischer S, Marti HH, and Preissner KT
- Subjects
- Humans, Neuroinflammatory Diseases, Brain metabolism, Alarmins metabolism, Nucleic Acids metabolism, MicroRNAs genetics, Neurodegenerative Diseases genetics
- Abstract
Neurological disorders such as stroke, multiple sclerosis, as well as the neurodegenerative diseases Parkinson's or Alzheimer's disease are accompanied or even powered by danger associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue. Besides protein-related DAMPs or "alarmins", numerous nucleic acid DAMPs exist in body fluids, such as cell-free nuclear and mitochondrial DNA as well as different species of extracellular RNA, collectively termed as self-extracellular nucleic acids (SENAs). Among these, microRNA, long non-coding RNAs, circular RNAs and extracellular ribosomal RNA constitute the majority of RNA-based DAMPs. Upon tissue injury, necrosis or apoptosis, such SENAs are released from neuronal, immune and other cells predominantly in association with extracellular vesicles and may be translocated to target cells where they can induce intracellular regulatory pathways in gene transcription and translation. The majority of SENA-induced signaling reactions in the brain appear to be related to neuroinflammatory processes, often causally associated with the onset or progression of the respective disease. In this review, the impact of the diverse types of SENAs on neuroinflammatory and neurodegenerative diseases will be discussed. Based on the accumulating knowledge in this field, several specific antagonistic approaches are presented that could serve as therapeutic interventions to lower the pathological outcome of the indicated brain disorders., (© 2023. National Science Council of the Republic of China (Taiwan).)
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- 2023
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39. Staphylococcus aureus extracellular adherence protein (Eap) reduces immune cell phenotype in developing but not in established atherosclerotic lesions.
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Salzmann M, Platzer H, Mussbacher M, Derler M, Lenz M, Haider P, Brekalo M, Kral-Pointner JB, Kastl S, Speidl WS, Preissner KT, Schubert U, Bischoff M, Uhrin P, Wojta J, and Hohensinner PJ
- Subjects
- Mice, Animals, Intercellular Adhesion Molecule-1 genetics, Staphylococcus aureus metabolism, Endothelial Cells metabolism, Lymphocyte Function-Associated Antigen-1 genetics, Phenotype, Atherosclerosis, Plaque, Atherosclerotic
- Abstract
Atherosclerosis is a chronic, inflammatory disease of the vessel wall where triggered immune cells bind to inflamed endothelium, extravasate and sustain local inflammation. Leukocyte adhesion and extravasation are mediated by adhesion molecules expressed by activated endothelial cells, like intercellular adhesion molecule 1 (ICAM-1). Extracellular adherence protein (Eap) from Staphylococcus aureus binds to a plethora of extracellular matrix proteins, including ICAM-1 and its ligands macrophage-1 antigen (Mac-1, α
M β2 ) and lymphocyte function-associated antigen 1 (LFA-1, αL β2 ), thereby disrupting the interaction between leukocytes and endothelial cells. We aimed to use Eap to inhibit the interaction of leukocytes with activated endothelial cells in settings of developing and established atherosclerosis in apolipoprotein E (ApoE) deficient mice on high-fat diet. In developing atherosclerosis, Eap treatment reduced circulating platelet-neutrophil aggregates as well as infiltration of T cells and neutrophils into the growing plaque, accompanied by reduced formation of neutrophil extracellular traps (NETs). However, plaque size did not change. Intervention treatment with Eap of already established plaques did not result in cellular or morphological plaque changes, whereas T cell infiltration was increased and thereby again modulated by Eap. We conclude that although Eap leads to cellular changes in developing plaques, clinical implications might be limited as patients are usually treated at a more advanced stage of disease progression. Hence, usage of Eap might be an interesting mechanistic tool for cellular infiltration during plaque development in basic research but not a clinical target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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40. Functions and cellular signaling by ribosomal extracellular RNA (rexRNA): Facts and hypotheses on a non-typical DAMP.
- Author
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Preissner KT and Fischer S
- Subjects
- Immunity, Innate, Receptors, Pattern Recognition metabolism, RNA genetics, Alarmins genetics, RNA, Ribosomal genetics, Pathogen-Associated Molecular Pattern Molecules
- Abstract
Upon microbial infections with the subsequent host response of innate immunity, a variety of fragmented RNA- and DNA-based "Pathogen-associated molecular patterns" (PAMPs) are recognized mainly by endosomal or cytoplasmic host cell "Pattern recognition receptors" (PRRs), particularly "Toll-like receptors" (TLRs). Concomitantly, various self-extracellular RNA species (exRNAs) are present in extracellular body fluids where they contribute to diverse physiological and homeostatic processes. In principle, such exRNAs, including the most abundant one, ribosomal exRNA (rexRNA), are designated as "Danger-associated molecular patterns" (DAMPs) and are prevented by e.g. natural modifications from uncontrolled signaling via TLRs to avoid hyper-inflammatory responses or autoimmunity. Upon cellular stress or tissue damage/necrosis, the levels and composition of released self-exRNA species, either in free form, in complex with proteins or in association with extracellular vesicles (EVs), can change considerably. Among the self-exRNAs, rexRNA is considered as a non-typical DAMP, since it may induce inflammatory responses by cell membrane receptors, both in the absence or presence of PAMPs. Yet, its mode of receptor activation to mount inflammatory responses remains obscure. RexRNA also serves as a universal damaging factor in cardiovascular and other diseases independent of PRRs. In general, RNase1 provides a profound antagonist in these pathologies and in rexRNA-mediated inflammatory cell responses. Based on the extrapolation of the here described aspects of rexRNA-biology, further activities of this molecular entity are hypothesized that may stimulate additional research in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2023
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41. Cobra Venom Factor Boosts Arteriogenesis in Mice.
- Author
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Götz P, Azubuike-Osu SO, Braumandl A, Arnholdt C, Kübler M, Richter L, Lasch M, Bobrowski L, Preissner KT, and Deindl E
- Subjects
- Animals, Hindlimb blood supply, Mice, Mice, Inbred C57BL, Neovascularization, Physiologic physiology, Elapid Venoms metabolism, Elapid Venoms pharmacology, Femoral Artery metabolism
- Abstract
Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU
+ ) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+ /MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.- Published
- 2022
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42. Extracellular Ribosomal RNA Acts Synergistically with Toll-like Receptor 2 Agonists to Promote Inflammation.
- Author
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Grote K, Nicolai M, Schubert U, Schieffer B, Troidl C, Preissner KT, Bauer S, and Fischer S
- Subjects
- Alarmins, Animals, Inflammation, Interleukin-6 genetics, Mice, Mice, Inbred C57BL, Oligopeptides, RNA, Ribosomal, 18S, Toll-Like Receptor 9 agonists, Toll-Like Receptor 2 agonists, Toll-Like Receptor 2 metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Self-extracellular RNA (eRNA), which is released under pathological conditions from damaged tissue, has recently been identified as a new alarmin and synergistic agent together with toll-like receptor (TLR)2 ligands to induce proinflammatory activities of immune cells. In this study, a detailed investigation of these interactions is reported. The macrophage cell line J774 A.1 or C57 BL/6 J wild-type mice were treated with 18S rRNA and different TLR2 agonists. Gene and protein expression of tumor necrosis factor (Tnf)-α ; interleukin (Il)-1β, Il-6 ; or monocyte chemoattractant protein (Mcp)-1 were analyzed and furthermore in vitro binding studies to TLR2 were performed. The TLR2/TLR6-agonist Pam
2 CSK4 (Pam2) together with 18S rRNA significantly increased the mRNA expression of inflammatory genes and the release of TNF-α from macrophages in a TLR2- and nuclear factor kappa B (NF-κB)-dependent manner. The injection of 18S rRNA/Pam2 into mice increased the cytokine levels of TNF-α, IL-6, and MCP-1 in the peritoneal lavage. Mechanistically, 18S rRNA built complexes with Pam2 and thus enhanced the affinity of Pam2 to TLR2. These results indicate that the alarmin eRNA, mainly consisting of rRNA, sensitizes TLR2 to enhance the innate immune response under pathological conditions. Thus, rRNA might serve as a new target for the treatments of bacterial and viral infections.- Published
- 2022
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43. Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19.
- Author
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Wygrecka M, Birnhuber A, Seeliger B, Michalick L, Pak O, Schultz AS, Schramm F, Zacharias M, Gorkiewicz G, David S, Welte T, Schmidt JJ, Weissmann N, Schermuly RT, Barreto G, Schaefer L, Markart P, Brack MC, Hippenstiel S, Kurth F, Sander LE, Witzenrath M, Kuebler WM, Kwapiszewska G, and Preissner KT
- Subjects
- Fibrin, Fibrinolysis, Humans, SARS-CoV-2, COVID-19, Thrombosis etiology
- Abstract
The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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44. Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals.
- Author
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Fischer S, Nasyrov E, Brosien M, Preissner KT, Marti HH, and Kunze R
- Subjects
- Animals, Mice, Stroke pathology, Alarmins immunology, Astrocytes immunology, Inflammation immunology, RNA immunology, Stroke immunology
- Abstract
Objective: Astrocytes participate in the local innate immune response of the central nervous system. In response to stress such as ischemia, activated cells release endogenous factors known as damage-associated molecular patterns (DAMPs). Self-extracellular RNA (eRNA) is such a ubiquitous alarm signal. However, it is unclear whether eRNA is involved in the early acute phase of cerebral ischemia and is sufficient to sensitize astrocytes towards a DAMP or PAMP (pathogen-associated molecular pattern) reaction., Methods: Pro-inflammatory activation upon eRNA stimulation was characterized in primary murine astrocyte cultures. In vivo, an experimental stroke model was used to localize and quantify eRNA in murine brain sections. Using primary cortical neurons and the mouse hippocampal neuronal cell line HT-22, neuronal RNA release upon stress conditions related to cerebral hypoxia/ischemia was analyzed., Results: While low-dose eRNA alone did not promote pro-inflammatory activation of astrocytes in culture, it strongly enhanced the expression of pro-inflammatory cytokines in the presence of either Pam2CSK4, a synthetic PAMP molecule that mimics bacterial infection, or high mobility group box 1 (HMGB1), a prominent DAMP. Synergism of eRNA/Pam2CSK4 and eRNA/HMGB1 was prevented by blockage of the astroglial toll-like receptor (TLR)-2. Inhibition of NF-κB- and mitogen-activated protein kinase-dependent signaling pathways hampered eRNA/Pam2CSK4-mediated pro-inflammatory activation of astrocytes. In vivo, the amount of non-nuclear, presumably extracellular ribosomal RNA in close proximity to neurons significantly accumulated across the infarct core and peri-infarct areas that was accompanied by transcriptional up-regulation of various pro-inflammatory factors. Accordingly, the exposure of neurons to hypoxic/ischemic stress in vitro resulted in the release of eRNA, partly mediated by active cellular processes dependent on the cytosolic calcium level., Conclusion: The DAMP signal eRNA can sensitize astrocytes as active players in cerebral innate immunity towards exogenous and endogenous activators of inflammation (PAMPs and DAMPs) in a synergistic manner via TLR2-NF-κB-dependent signaling mechanisms. These findings provide new insights into the pathogenesis of ischemic stroke and other inflammatory neurological disorders. Further studies will clarify whether administration of RNase in vivo may serve as an effective treatment for inflammatory brain pathologies., (© 2021. The Author(s).)
- Published
- 2021
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45. More Is Not Always Better-the Double-Headed Role of Fibronectin in Staphylococcus aureus Host Cell Invasion.
- Author
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Niemann S, Nguyen MT, Eble JA, Chasan AI, Mrakovcic M, Böttcher RT, Preissner KT, Roßlenbroich S, Peters G, and Herrmann M
- Subjects
- A549 Cells, Adhesins, Bacterial metabolism, Cells, Cultured, Fibronectins genetics, Humans, Integrin alpha5beta1 genetics, Integrin alpha5beta1 metabolism, Phagocytosis, Staphylococcus aureus pathogenicity, Endothelial Cells microbiology, Fibronectins metabolism, Host Microbial Interactions, Osteoblasts microbiology, Staphylococcus aureus physiology
- Abstract
While Staphylococcus aureus has classically been considered an extracellular pathogen, these bacteria are also capable of being taken up by host cells, including nonprofessional phagocytes such as endothelial cells, epithelial cells, or osteoblasts. The intracellular S. aureus lifestyle contributes to infection development. The predominant recognition and internalization pathway appears to be the binding of the bacteria via a fibronectin bridge to the α5β1-integrin on the host cell membrane, followed by phagocytosis. Although osteoblasts showed high expression of α5β1-integrin and fibronectin, and bacteria adhered to osteoblasts to a high proportion, here we demonstrate by internalization assays and immunofluorescence microscopy that S. aureus was less engulfed in osteoblasts than in epithelial cells. The addition of exogenous fibronectin during the infection of cells with S. aureus resulted in an increased uptake by epithelial cells but not by osteoblasts. This contrasts with the previous conception of the uptake mechanism, where high expression of integrin and fibronectin would promote the bacterial uptake into host cells. Extracellular fibronectin surrounding osteoblasts, but not epithelial cells, is organized in a fibrillary network. The inhibition of fibril formation, the short interfering RNA-mediated reduction of fibronectin expression, and the disruption of the fibronectin-fibril meshwork all resulted in a significant increase in S. aureus uptake by osteoblasts. Thus, the network of fibronectin fibrils appears to strongly reduce the uptake of S. aureus into a given host cell, indicating that the supramolecular structure of fibronectin determines the capacity of particular host cells to internalize the pathogen. IMPORTANCE Traditionally, Staphylococcus aureus has been considered an extracellular pathogen. However, among other factors, the frequent failure of antimicrobial therapy and the ability of the pathogen to cause recurrent disease have established the concept of eukaryotic invasion of the pathogen, thereby evading the host's immune system. In the current model of host cell invasion, bacteria initially bind to α5β1 integrin on the host cell side via a fibronectin bridge, which eventually leads to phagocytosis of S. aureus by host cells. However, in this study, we demonstrate that not the crude amount but the supramolecular structure of fibronectin molecules deposited on the eukaryotic cell surface plays an essential role in bacterial uptake by host cells. Our findings explain the large differences of S. aureus uptake efficacy in different host cell types as well as in vivo differences between courses of bacterial infections and the localization of bacteria in different clinical settings.
- Published
- 2021
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46. The Absence of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) Promotes Pro-Angiogenic Microenvironmental Conditions and Angiogenesis in Muscle Tissue Ischemia.
- Author
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Kübler M, Beck S, Peffenköver LL, Götz P, Ishikawa-Ankerhold H, Preissner KT, Fischer S, Lasch M, and Deindl E
- Subjects
- Animals, Disease Models, Animal, Endothelial Cells metabolism, Extracellular Traps metabolism, Inflammation pathology, Ischemia metabolism, Leukocyte Count, Leukocytes metabolism, Macrophage Activation, Macrophages metabolism, Male, Mice, Mice, 129 Strain, Muscles metabolism, Neutrophils metabolism, RNA-Binding Proteins physiology, Ischemia pathology, Neovascularization, Physiologic physiology, RNA-Binding Proteins metabolism
- Abstract
Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31
+ /CD45- /BrdU+ ). This was accompanied by a reduction of total leukocyte count (CD45+ ), neutrophils (MPO+ ), neutrophil extracellular traps (NETs) (MPO+ CitH3+ ), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68+ /MRC1- ) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68+ /MRC1+ ) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia.- Published
- 2021
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47. Platelet glycoprotein VI-dependent thrombus stabilization is essential for the intraportal engraftment of pancreatic islets.
- Author
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Chen C, Rawat D, Samikannu B, Bender M, Preissner KT, and Linn T
- Subjects
- Animals, Blood Platelets, Mice, Platelet Activation, Platelet Membrane Glycoproteins, Islets of Langerhans, Thrombosis etiology
- Abstract
Platelet activation and thrombus formation have been implicated to be detrimental for intraportal pancreatic islet transplants. The platelet-specific collagen receptor glycoprotein VI (GPVI) plays a key role in thrombosis through cellular activation and the subsequent release of secondary mediators. In aggregometry and in a microfluidic dynamic assay system modeling flow in the portal vein, pancreatic islets promoted platelet aggregation and triggered thrombus formation, respectively. While platelet GPVI deficiency did not affect the initiation of these events, it was found to destabilize platelet aggregates and thrombi in this process. Interestingly, while no major difference was detected in early thrombus formation after intraportal islet transplantation, genetic GPVI deficiency or acute anti-GPVI treatment led to an inferior graft survival and function in both syngeneic mouse islet transplantation and xenogeneic human islet transplantation models. These results demonstrate that platelet GPVI signaling is indispensable in stable thrombus formation induced by pancreatic islets. GPVI deficiency resulted in thrombus destabilization and inferior islet engraftment indicating that thrombus formation is necessary for a successful intraportal islet transplantation in which platelets are active modulators., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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48. NK Cell-mediated Neuroblastoma Cell Lysis is Enhanced by IgG From Patients With Pediatric Opsoclonus-Myoclonus Syndrome.
- Author
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Zar T, Tschernatsch M, Hero B, Lang B, Preissner KT, and Blaes F
- Subjects
- Autoantibodies blood, Autoantibodies drug effects, Child, Preschool, Female, Follow-Up Studies, Humans, Immunoglobulin G immunology, Infant, Killer Cells, Natural immunology, Male, Neuroblastoma blood, Neuroblastoma complications, Neuroblastoma immunology, Opsoclonus-Myoclonus Syndrome blood, Opsoclonus-Myoclonus Syndrome complications, Opsoclonus-Myoclonus Syndrome immunology, Prognosis, Apoptosis, Autoantibodies immunology, Immunoglobulin G adverse effects, Killer Cells, Natural pathology, Neuroblastoma pathology, Opsoclonus-Myoclonus Syndrome pathology
- Abstract
Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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49. Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis.
- Author
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Sharma S, Hofbauer TM, Ondracek AS, Chausheva S, Alimohammadi A, Artner T, Panzenboeck A, Rinderer J, Shafran I, Mangold A, Winker R, Wohlschläger-Krenn E, Moser B, Taghavi S, Klepetko W, Preissner KT, and Lang IM
- Subjects
- Animals, Cells, Cultured, Chronic Disease, Female, Fibrosis, Humans, Male, Mice, Middle Aged, Extracellular Traps, Hypertension, Pulmonary pathology, Neutrophils pathology, Pulmonary Embolism pathology, Thrombosis pathology
- Abstract
Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-β (TGF-β) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-β overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-β signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae., (© 2021 by The American Society of Hematology.)
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- 2021
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50. Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation.
- Author
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Dobersch S, Rubio K, Singh I, Günther S, Graumann J, Cordero J, Castillo-Negrete R, Huynh MB, Mehta A, Braubach P, Cabrera-Fuentes H, Bernhagen J, Chao CM, Bellusci S, Günther A, Preissner KT, Kugel S, Dobreva G, Wygrecka M, Braun T, Papy-Garcia D, and Barreto G
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins metabolism, Chromatin chemistry, Chromatin metabolism, HEK293 Cells, HMGA2 Protein metabolism, Histones metabolism, Humans, Idiopathic Pulmonary Fibrosis genetics, Idiopathic Pulmonary Fibrosis pathology, Mice, Phosphorylation, Phosphoserine metabolism, RNA Polymerase II metabolism, Transcription Initiation Site, Transcriptional Activation genetics, Transforming Growth Factor beta1 metabolism, DNA Demethylation, Nucleosomes metabolism, Transcription Initiation, Genetic
- Abstract
In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.
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- 2021
- Full Text
- View/download PDF
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