Publications by authors named "Liliana Schaefer"

138 Publications

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19.

Blood Adv 2021 Dec 3. Epub 2021 Dec 3.

Justus-Liebig-University, Medical School, Giessen, Germany.

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in critically ill COVID-19 patients in comparison to patients with severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report 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 ARDS-influenza. Using confocal and electron microscopy, we showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers 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 ARDS-infleunza subjects. Dysregulatated 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 wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19 patients. Together, compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to high incidence of thrombotic events in COVID-19.
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http://dx.doi.org/10.1182/bloodadvances.2021004816DOI Listing
December 2021

The basement membrane in the cross-roads between the lung and kidney.

Matrix Biol 2021 Nov 25. Epub 2021 Nov 25.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Otto Loewi Research Center, Department of Physiology, Medical University of Graz, Graz, Austria; Institute for Lung Health (ILH), Giessen, Germany.. Electronic address:

The basement membrane (BM) is a specialized layer of extracellular matrix components that plays a central role in maintaining lung and kidney functions. Although the composition of the BM is usually tissue specific, the lung and the kidney preferentially use similar BM components. Unsurprisingly, diseases with BM defects often have severe pulmonary or renal manifestations, sometimes both. Excessive remodeling of the BM, which is a hallmark of both inflammatory and fibrosing diseases in the lung and the kidney, can lead to the release of BM-derived matrikines, proteolytic fragments with distinct biological functions. These matrikines can then influence disease activity at the site of liberation. However, they are also released to the circulation, where they can directly affect the vascular endothelium or target other organs, leading to extrapulmonary or extrarenal manifestations. In this review, we will summarize the current knowledge of the composition and function of the BM and its matrikines in health and disease, both in the lung and in the kidney. By comparison, we will highlight, why the BM and its matrikines may be central in establishing a renal-pulmonary interaction axis.
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http://dx.doi.org/10.1016/j.matbio.2021.11.003DOI Listing
November 2021

Extracellular Matrix Remodeling in Chronic Liver Disease.

Curr Tissue Microenviron Rep 2021 Jul 23:1-12. Epub 2021 Jul 23.

Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Purpose Of The Review: This review aims to summarize the current knowledge of the extracellular matrix remodeling during hepatic fibrosis. We discuss the diverse interactions of the extracellular matrix with hepatic cells and the surrounding matrix in liver fibrosis, with the focus on the molecular pathways and the mechanisms that regulate extracellular matrix remodeling.

Recent Findings: The extracellular matrix not only provides structure and support for the cells, but also controls cell behavior by providing adhesion signals and by acting as a reservoir of growth factors and cytokines.

Summary: Hepatic fibrosis is characterized by an excessive accumulation of extracellular matrix. During fibrogenesis, the natural remodeling process of the extracellular matrix varies, resulting in the excessive accumulation of its components, mainly collagens. Signals released by the extracellular matrix induce the activation of hepatic stellate cells, which are the major source of extracellular matrix and most abundant myofibroblasts in the liver.

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http://dx.doi.org/10.1007/s43152-021-00030-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300084PMC
July 2021

Sex-specific differences in plasma levels of FXII, HK, and FXIIa-C1-esterase inhibitor complexes in community-acquired pneumonia.

Am J Physiol Lung Cell Mol Physiol 2021 10 28;321(4):L764-L774. Epub 2021 Jul 28.

Center for Infection and Genomics of the Lung, Universities of Giessen and Marburg Lung Center, Giessen, Germany.

Sex-dependent differences in immunity and coagulation play an active role in the outcome of community-acquired pneumonia (CAP). Contact phase proteins act at the crossroads between inflammation and coagulation thus representing a point of convergence in host defense against infection. Here, we measured the levels of factor XII (FXII), FXIIa-C1 esterase inhibitor (C1INH) complexes, and high-molecular-weight kininogen (HK) in plasma of patients with CAP and correlated them to clinical disease severity. Levels of FXIIa-C1INH/albumin ratio were elevated, irrespective of sex, in plasma of patients with CAP ( = 139) as compared with age-matched donors ( = 58). No simultaneous decrease in FXII levels, indicating its consumption, was observed. Stratification by sex revealed augmented FXII levels in plasma of women with CAP as compared with sex-matched donors yet no apparent differences in men. This sex-specific effect was, however, attributable to lower FXII levels in female donors relative to men donors. Plasma estradiol levels mirrored those for FXII. Levels of HK/albumin ratio were decreased in CAP plasma as compared with donors, however, after stratification by sex, this difference was only observed in women and was related to higher HK/albumin values in female donors as opposed to male donors. Finally, strong negative correlation between plasma levels of HK/albumin ratio and CAP severity, as assessed by CRB65 score, in males and females was observed. Our study identifies sex-dependent differences in plasma levels of the contact phase proteins in elderly subjects that may contribute to specific clinical outcomes in CAP between men and women.
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http://dx.doi.org/10.1152/ajplung.00162.2021DOI Listing
October 2021

Autophagy: Instructions from the extracellular matrix.

Matrix Biol 2021 06 2;100-101:1-8. Epub 2021 Jul 2.

Institute of Biochemistry II, School of Medicine, Goethe University, Frankfurt, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany. Electronic address:

In recent years, extensive research has uncovered crucial regulatory roles for the extracellular matrix (ECM) in regulating autophagy. Autophagy is a ubiquitous and highly conserved catabolic process that allows the selective removal and recycling of cytosolic components via lysosomal or vacuolar degradation. Due to its pivotal role in cellular homeostasis, the impairment of autophagy is involved in the pathophysiology of numerous diseases, comprising infectious diseases, immune and neurodegenerative disorders, renal and hepatic diseases, intervertebral and cartilage disorders, as well as fibrosis and cancer. Several ECM-derived proteoglycans and proteins, including decorin, biglycan, endorepellin, endostatin, collagen VI, and plasminogen kringle 5, have been identified as strong inducers of autophagy. In contrast, laminin α2, perlecan, and lumican exert opposite function by suppressing autophagy. Importantly, by direct interaction with various receptors, which interplay with their co-receptors and adhesion molecules, the ECM is able to direct autophagy in a molecular and cell context-specific manner. Thus, vast pharmacological potential resides in translating this knowledge into the development of ECM-derived therapeutics selectively regulating autophagy.
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http://dx.doi.org/10.1016/j.matbio.2021.06.002DOI Listing
June 2021

Biglycan: A regulator of hepatorenal inflammation and autophagy.

Matrix Biol 2021 06 10;100-101:150-161. Epub 2021 Jun 10.

Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany. Electronic address:

Soluble biglycan, a small leucine-rich proteoglycan, plays a significant role in several pathologies as it has emerged as an extracellular matrix-derived danger-associated molecular pattern. Biglycan is released from the extracellular matrix in response to tissue injury and, as a canonical danger signal, interacts with innate immune receptors, Toll-like receptors 2 and 4, thereby triggering a sustained inflammatory response. Recent evidence indicates that biglycan acts as a molecular switch between inflammation and autophagy by a specific interaction with the Toll-like co-receptor CD14 and CD44, respectively. Biglycan-evoked autophagy further contributes to the anti-inflammatory M2 macrophage polarization, inflammation resolution and tissue repair. These multivalent roles of soluble biglycan have been well characterized in inflammatory kidney diseases. In chronic liver diseases, increased levels of soluble biglycan have been described for years, leading to utilization of biglycan serum levels as a non-invasive biomarker for fibrosis. Hepatorenal dysfunction represents a classic example of inter-organ crosstalk, in which functional and molecular alterations of the cirrhotic liver can promote the development of renal failure. In patients with liver cirrhosis, development of hepatorenal syndrome is associated with high mortality. In this review, we will discuss the crucial role of soluble biglycan in inflammation and autophagy and its possible implications for hepatorenal dysfunction. We propose a novel concept of hepatorenal crosstalk, that is, biglycan produced by the cirrhotic liver could constitute a circulating "messenger" for the kidneys triggering inflammation and/or autophagy ultimately affecting disease outcome.
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http://dx.doi.org/10.1016/j.matbio.2021.06.001DOI Listing
June 2021

Welcome from the new Editor-in-Chief.

Authors:
Liliana Schaefer

Am J Physiol Cell Physiol 2021 07 26;321(1):C1-C2. Epub 2021 May 26.

Institute of Pharmacology and Toxicology, Goethe University, Frankfurt/Main, Frankfurt, Germany.

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http://dx.doi.org/10.1152/ajpcell.00181.2021DOI Listing
July 2021

Loss of sphingosine kinase 2 enhances Wilm's tumor suppressor gene 1 and nephrin expression in podocytes and protects from streptozotocin-induced podocytopathy and albuminuria in mice.

Matrix Biol 2021 04 17;98:32-48. Epub 2021 May 17.

Institute of Pharmacology, University of Bern, Inselspital, INO-F, Bern CH-3010, Switzerland. Electronic address:

The sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that is now appreciated as key regulatory factor for various cellular functions in the kidney, including matrix remodeling. It is generated by two sphingosine kinases (Sphk), Sphk1 and Sphk2, which are ubiquitously expressed, but have distinct enzymatic activities and subcellular localizations. In this study, we have investigated the role of Sphk2 in podocyte function and its contribution to diabetic nephropathy. We show that streptozotocin (STZ)-induced nephropathy and albuminuria in mice is prevented by genetic depletion of Sphk2. This protection correlated with an increased protein expression of the transcription factor Wilm's tumor suppressor gene 1 (WT1) and its target gene nephrin, and a reduced macrophage infiltration in immunohistochemical renal sections of STZ-treated Sphk2 mice compared to STZ-treated wildtype mice. To investigate changes on the cellular level, we used an immortalized human podocyte cell line and generated a stable knockdown of Sphk2 (Sphk2-kd) by a lentiviral transduction method. These Sphk2-kd cells accumulated sphingosine as a consequence of the knockdown, and showed enhanced nephrin and WT1 mRNA and protein expressions similar to the finding in Sphk2 knockout mice. Treatment of wildtype podocytes with the highly selective Sphk2 inhibitor SLM6031434 caused a similar upregulation of nephrin and WT1 expression. Furthermore, exposing cells to the profibrotic mediator transforming growth factor β (TGFβ) resulted on the one side in reduced nephrin and WT1 expression, but on the other side, in upregulation of various profibrotic marker proteins, including connective tissue growth factor (CTGF), fibronectin (FN) and plasminogen activator inhibitor (PAI) 1. All these effects were reverted by Sphk2-kd and SLM6031434. Mechanistically, the protection by Sphk2-kd may depend on accumulated sphingosine and inhibited PKC activity, since treatment of cells with exogenous sphingosine not only reduced the phosphorylation pattern of PKC substrates, but also increased WT1 protein expression. Moreover, the selective stable knockdown of PKCδ increased WT1 expression, suggesting the involvement of this PKC isoenzyme in WT1 regulation. The glucocorticoid dexamethasone, which is a treatment option in many glomerular diseases and is known to mediate a nephroprotection, not only downregulated Sphk2 and enhanced cellular sphingosine, but also enhanced WT1 and nephrin expressions, thus, suggesting that parts of the nephroprotective effect of dexamethasone is mediated by Sphk2 downregulation. Altogether, our data demonstrated that loss of Sphk2 is protective in diabetes-induced podocytopathy and can prevent proteinuria, which is a hallmark of many glomerular diseases. Thus, Sphk2 could serve as a new attractive pharmacological target to treat proteinuric kidney diseases.
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http://dx.doi.org/10.1016/j.matbio.2021.05.003DOI Listing
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Validation of highly selective sphingosine kinase 2 inhibitors SLM6031434 and HWG-35D as effective anti-fibrotic treatment options in a mouse model of tubulointerstitial fibrosis.

Cell Signal 2021 03 8;79:109881. Epub 2020 Dec 8.

Pharmazentrum Frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Universitätsklinikum and Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Renal fibrosis is characterized by chronic inflammation and excessive accumulation of extracellular matrix and progressively leads to functional insufficiency and even total loss of kidney function. In this study we investigated the anti-fibrotic potential of two highly selective and potent SK2 inhibitors, SLM6031434 and HWG-35D, in unilateral ureter obstruction (UUO), a model for progressive renal fibrosis, in mice. In both cases, treatment with SLM6031434 or HWG-35D resulted in an attenuated fibrotic response to UUO in comparison to vehicle-treated mice as demonstrated by reduced collagen accumulation and a decreased expression of collagen-1 (Col1), fibronectin-1 (FN-1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA). Similar to our previous study in Sphk2 mice, we found an increased protein expression of Smad7, a negative regulator of the pro-fibrotic TGFβ/Smad signalling cascade, accompanied by a strong accumulation of sphingosine in SK2 inhibitor-treated kidneys. Treatment of primary renal fibroblasts with SLM6031434 or HWG-35D dose-dependently increased Smad7 expression and ameliorated the expression of Col1, FN-1 and CTGF. In summary, these data prove the anti-fibrotic potential of SK2 inhibition in a mouse model of renal fibrosis, thereby validating SK2 as pharmacological target for the treatment of fibrosis in chronic kidney disease.
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http://dx.doi.org/10.1016/j.cellsig.2020.109881DOI Listing
March 2021

Consistent alteration of chain length-specific ceramides in human and mouse fibrotic kidneys.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 01 1;1866(1):158821. Epub 2020 Oct 1.

Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, Germany.

Background: Several studies revealed alterations of single sphingolipid species, such as chain length-specific ceramides, in plasma and serum of patients with kidney diseases. Here, we investigated whether such alterations occur in kidney tissue from patients and mice suffering from renal fibrosis, the common endpoint of chronic kidney diseases.

Methods: Human fibrotic kidney samples were collected from nephrectomy specimens with hydronephrosis and/or pyelonephritis. Healthy parts from tumor nephrectomies served as nonfibrotic controls. Mouse fibrotic kidney samples were collected from male C57BL/6J mice treated with an adenine-rich diet for 14 days or were subjected to 7 days of unilateral ureteral obstruction (UUO). Kidneys of untreated mice and contralateral kidneys (UUO) served as respective controls. Sphingolipid levels were detected by LC-MS/MS. Fibrotic markers were analyzed by TaqMan® analysis and immunohistology.

Results: Very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 were significantly downregulated in both fibrotic human kidney cortex and fibrotic murine kidney compared to respective control samples. These effects correlate with upregulation of COL1α1, COL3α1 and αSMA expression in fibrotic human kidney cortex and fibrotic mouse kidney.

Conclusion: We have shown that very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 are consistently downregulated in fibrotic kidney samples from human and mouse. Our findings support the use of in vivo murine models as appropriate translational means to understand the involvement of ceramides in human kidney diseases. In addition, our study raises interesting questions about the possible manipulation of ceramide metabolism to prevent progression of fibrosis and the use of ceramides as potential biomarkers of chronic kidney disease.
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http://dx.doi.org/10.1016/j.bbalip.2020.158821DOI Listing
January 2021

The Role of Macrophage-Inducible C-Type Lectin in Different Stages of Chronic Liver Disease.

Front Immunol 2020 7;11:1352. Epub 2020 Jul 7.

Department of Internal Medicine I, University Hospital, Goethe University, Frankfurt, Germany.

The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.
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http://dx.doi.org/10.3389/fimmu.2020.01352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358277PMC
April 2021

Podocyte Integrin- and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy.

J Am Soc Nephrol 2020 08 24;31(8):1762-1780. Epub 2020 Jul 24.

Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University Magdeburg, Magdeburg, Germany

Background: Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part the G protein-coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear.

Methods: A combination of approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP.

Results: The zymogen protein C and aPC bind to podocyte integrin- , a subunit of integrin- . Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin- induces transient binding of integrin- with G and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin- its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin- , aPC induces sustained RhoA activation, mimicking the effect of thrombin. , overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin- interaction by specifically deleting podocyte integrin- or by abolishing aPC's integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC's nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPC and wild-type mice. aPC-integrin- acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin- as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.
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http://dx.doi.org/10.1681/ASN.2019111163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460917PMC
August 2020

Communications via the Small Leucine-rich Proteoglycans: Molecular Specificity in Inflammation and Autoimmune Diseases.

J Histochem Cytochem 2020 12 6;68(12):887-906. Epub 2020 Jul 6.

Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.

Inflammation is a highly regulated biological response of the immune system that is triggered by assaulting pathogens or endogenous alarmins. It is now well established that some soluble extracellular matrix constituents, such as small leucine-rich proteoglycans (SLRPs), can act as danger signals and trigger aseptic inflammation by interacting with innate immune receptors. SLRP inflammatory signaling cascade goes far beyond its canonical function. By choosing specific innate immune receptors, coreceptors, and adaptor molecules, SLRPs promote a switch between pro- and anti-inflammatory signaling, thereby determining disease resolution or chronification. Moreover, by orchestrating signaling through various receptors, SLRPs fine-tune inflammation and, despite their structural homology, regulate inflammatory processes in a molecule-specific manner. Hence, the overarching theme of this review is to highlight the molecular and functional specificity of biglycan-, decorin-, lumican-, and fibromodulin-mediated signaling in inflammatory and autoimmune diseases.
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http://dx.doi.org/10.1369/0022155420930303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708667PMC
December 2020

Between life and death: Epithelial cells in lung pathologies.

Cell Signal 2020 08 20;72:109652. Epub 2020 Apr 20.

Institute of Pharmacology and Toxicology, Goethe University, Frankfurt Am Main, Germany.

Recent lineage tracing strategies, single-cell RNA sequencing approaches and high-resolution imaging identified remarkable heterogeneity of lung epithelial cells thus leaving open a question as to their specific functions in lung health and disease. Understanding the molecular mechanisms controlling lung epithelial cell morphogenesis and differentiation as well as communication with other cell types and extracellular matrix provides a basis for improving the outcome for patients with respiratory diseases. Although, the substantial progress has been made towards achieving this goal, we are still far away from being able to train/instruct lung epithelial cells in order to facilitate lung repair and regeneration. The special issue of the Cellular Signaling entitled "Between life and death: epithelial cells in lung pathologies" represents a blend of research articles and reviews, in which structural and functional diversities of lung epithelial cells in health and disease are discussed.
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http://dx.doi.org/10.1016/j.cellsig.2020.109652DOI Listing
August 2020

The product PACRG promotes TNF signaling by stabilizing LUBAC.

Sci Signal 2020 02 4;13(617). Epub 2020 Feb 4.

Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801 Bochum, Germany.

The (), which encodes a protein of unknown function, shares a bidirectional promoter with (), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor κB (NF-κB) activation in response to TNF. TNF-induced nuclear translocation of the NF-κB subunit p65 and NF-κB-dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-κB activation in the absence of PACRG was accompanied by a decrease in linear ubiquitylation mediated by the linear ubiquitin chain assembly complex (LUBAC), which is composed of the two E3 ubiquitin ligases HOIP and HOIL-1L and the adaptor protein SHARPIN. Upon TNF stimulation, PACRG was recruited to the activated TNF receptor complex and interacted with LUBAC components. PACRG functionally replaced SHARPIN in this context. In SHARPIN-deficient cells, PACRG prevented LUBAC destabilization, restored HOIP-dependent linear ubiquitylation, and protected cells from TNF-induced apoptosis. This function of PACRG in positively regulating TNF signaling may help to explain the association of and polymorphisms with an increased susceptibility to intracellular pathogens.
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http://dx.doi.org/10.1126/scisignal.aav1256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279956PMC
February 2020

Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-β1 from ECM stores.

Matrix Biol 2020 06 11;88:69-88. Epub 2019 Dec 11.

Departments of Biochemistry and Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:

In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-β1 from the extracellular matrix (ECM) stores. Liberation of active TGF-β1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.
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http://dx.doi.org/10.1016/j.matbio.2019.12.001DOI Listing
June 2020

Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.

Cell Signal 2020 01 3;65:109432. Epub 2019 Nov 3.

Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:

Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonstrate that PFD reduces proliferation, 2D- and 3D-migration as well as colony formation of the non-small-cell lung carcinoma (NSCLC) cells. On a molecular level, we show that PFD on the one hand interacts with plasminogen activator inhibitor-1 (PAI-1; K of 46.2±11.3nM) and affects its inhibitory potency, but on the other hand it also increases PAI-1 expression; in both cases consequently leading to the reduction of urokinase (uPA) activity. Finally, we report that the effect of PFD on 2D-migration of NSCLC cells depends on PAI-1 expression and thus on the activity of the uPA system whereas the PFD-induced changes in cancer cell proliferation, 3D-migration and colony formation are PAI-1 independent. To conclude, a direct interference of PFD with the uPA-PAI-1 system may deregulate pericellular proteolytic activity and thereby influence the stability of the tumor blood vessels and the matrix architecture within tumor stroma.
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http://dx.doi.org/10.1016/j.cellsig.2019.109432DOI Listing
January 2020

Renal Fibrosis: Common Enemy of Many Origins.

J Histochem Cytochem 2019 09;67(9):621

Goethe University Frankfurt, Frankfurt, Germany.

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http://dx.doi.org/10.1369/0022155419865531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713976PMC
September 2019

Danger matrix molecules orchestrate CD14/CD44 signaling in cancer development.

Semin Cancer Biol 2020 05 11;62:31-47. Epub 2019 Aug 11.

Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany. Electronic address:

The tumor matrix together with inflammation and autophagy are crucial regulators of cancer development. Embedded in the tumor stroma are numerous proteoglycans which, in their soluble form, act as danger-associated molecular patterns (DAMPs). By interacting with innate immune receptors, the Toll-like receptors (TLRs), DAMPs autonomously trigger aseptic inflammation and can regulate autophagy. Biglycan, a known danger proteoglycan, can regulate the cross-talk between inflammation and autophagy by evoking a switch between pro-inflammatory CD14 and pro-autophagic CD44 co-receptors for TLRs. Thus, these novel mechanistic insights provide some explanation for the plethora of reports indicating that the same matrix-derived DAMP acts either as a promoter or suppressor of tumor growth. In this review we will summarize and critically discuss the role of the matrix-derived DAMPs biglycan, hyaluronan, and versican in regulating the TLR-, CD14- and CD44-signaling dialogue between inflammation and autophagy with particular emphasis on cancer development.
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http://dx.doi.org/10.1016/j.semcancer.2019.07.026DOI Listing
May 2020

When Place Matters: Shuttling of Enolase-1 Across Cellular Compartments.

Front Cell Dev Biol 2019 26;7:61. Epub 2019 Apr 26.

Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.

Enolase is a glycolytic enzyme, which catalyzes the inter-conversion of 2-phosphoglycerate to phosphoenolpyruvate. Altered expression of this enzyme is frequently observed in cancer and accounts for the Warburg effect, an adaptive response of tumor cells to hypoxia. In addition to its catalytic function, ENO-1 exhibits other activities, which strongly depend on its cellular and extracellular localization. For example, the association of ENO-1 with mitochondria membrane was found to be important for the stability of the mitochondrial membrane, and ENO-1 sequestration on the cell surface was crucial for plasmin-mediated pericellular proteolysis. The latter activity of ENO-1 enables many pathogens but also immune and cancer cells to invade the tissue, leading further to infection, inflammation or metastasis formation. The ability of ENO-1 to conduct so many diverse processes is reflected by its contribution to a high number of pathologies, including type 2 diabetes, cardiovascular hypertrophy, fungal and bacterial infections, cancer, systemic lupus erythematosus, hepatic fibrosis, Alzheimer's disease, rheumatoid arthritis, and systemic sclerosis. These unexpected non-catalytic functions of ENO-1 and their contributions to diseases are the subjects of this review.
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http://dx.doi.org/10.3389/fcell.2019.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498095PMC
April 2019

Lipids - two sides of the same coin in lung fibrosis.

Cell Signal 2019 08 15;60:65-80. Epub 2019 Apr 15.

Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive extracellular matrix deposition in the lung parenchyma leading to the destruction of lung structure, respiratory failure and premature death. Recent studies revealed that the pathogenesis of IPF is associated with alterations in the synthesis and the activity of lipids, lipid regulating proteins and cell membrane lipid transporters and receptors in different lung cells. Furthermore, deregulated lipid metabolism was found to contribute to the profibrotic phenotypes of lung fibroblasts and alveolar epithelial cells. Consequently, several pharmacological agents, targeting lipids, lipid mediators, and lipoprotein receptors, was successfully tested in the animal models of lung fibrosis and entered early phase clinical trials. In this review, we highlight new therapeutic options to counteract disturbed lipid hemostasis in the maladaptive lung remodeling.
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http://dx.doi.org/10.1016/j.cellsig.2019.04.007DOI Listing
August 2019

LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension.

Biochim Biophys Acta Mol Basis Dis 2019 06 22;1865(6):1604-1616. Epub 2019 Mar 22.

Department of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:

Pulmonary hypertension (PH) is characterized by a thickening of the distal pulmonary arteries caused by medial hypertrophy, intimal proliferation and vascular fibrosis. Low density lipoprotein receptor-related protein 1 (LRP1) maintains vascular homeostasis by mediating endocytosis of numerous ligands and by initiating and regulating signaling pathways. Here, we demonstrate the increased levels of LRP1 protein in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline-treated rats. Platelet-derived growth factor (PDGF)-BB upregulated LRP1 expression in pulmonary artery smooth muscle cells (PASMC). This effect was reversed by the PDGF-BB neutralizing antibody or the PDGF receptor antagonist. Depletion of LRP1 decreased proliferation of donor and IPAH PASMC in a β1-integrin-dependent manner. Furthermore, LRP1 silencing attenuated the expression of fibronectin and collagen I and increased the levels of α-smooth muscle actin and myocardin in donor, but not in IPAH, PASMC. In addition, smooth muscle cell (SMC)-specific LRP1 knockout augmented α-SMA expression in pulmonary vessels and reduced SMC proliferation in 3D ex vivo murine lung tissue cultures. In conclusion, our results indicate that LRP1 promotes the dedifferentiation of PASMC from a contractile to a synthetic phenotype thus suggesting its contribution to vascular remodeling in PH.
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http://dx.doi.org/10.1016/j.bbadis.2019.03.012DOI Listing
June 2019

Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy.

FEBS J 2019 08 27;286(15):2965-2979. Epub 2019 Feb 27.

Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.

It is well established that biglycan, a small leucine-rich proteoglycan, acts as an extracellular matrix-derived danger signal in its soluble form. By binding to innate immunity Toll-like receptors (TLR) 2 and 4, biglycan initiates and perpetuates the inflammatory response. Previous work has conveyed that biglycan's role in inflammation extends far beyond its function as a canonical danger signal. It has been shown that biglycan acts in an anti-inflammatory capacity, wherein it tightly regulates the inflammatory response. In this review, we will discuss a paradigm shift to our understanding of biglycan signaling in inflammation. Mounting evidence suggests that the selective interactions between biglycan, TLRs, and their adapter proteins critically regulate downstream signaling and disease outcome. Biglycan can act as a high-affinity ligand for TLR coreceptors CD14 and CD44, further providing an additional layer of complexity. We propose a novel concept, that biglycan steers signaling toward inflammation by interacting with CD14, whereas it can trigger autophagy by binding to CD44. Thus, biglycan, and perhaps others soluble proteoglycans, could function as molecular switches which could either propagate the signaling of chronic inflammation or promote the resolution of inflammatory processes. Obviously, these new functions have broad implications in the regulation of various inflammatory diseases and could provide the basis for developing novel therapeutic regimens that would selectively target the interactions between biglycan, TLRs, coreceptors, and adapter molecules.
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http://dx.doi.org/10.1111/febs.14791DOI Listing
August 2019

Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury.

Kidney Int 2019 03 31;95(3):540-562. Epub 2019 Jan 31.

Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany. Electronic address:

Biglycan, a small leucine-rich proteoglycan, acts as a danger signal and is classically thought to promote macrophage recruitment via Toll-like receptors (TLR) 2 and 4. We have recently shown that biglycan signaling through TLR 2/4 and the CD14 co-receptor regulates inflammation, suggesting that TLR co-receptors may determine whether biglycan-TLR signaling is pro- or anti-inflammatory. Here, we sought to identify other co-receptors and characterize their impact on biglycan-TLR signaling. We found a marked increase in the number of autophagic macrophages in mice stably overexpressing soluble biglycan. In vitro, stimulation of murine macrophages with biglycan triggered autophagosome formation and enhanced the flux of autophagy markers. Soluble biglycan also promoted autophagy in human peripheral blood macrophages. Using macrophages from mice lacking TLR2 and/or TLR4, CD14, or CD44, we demonstrated that the pro-autophagy signal required TLR4 interaction with CD44, a receptor involved in adhesion, migration, lymphocyte activation, and angiogenesis. In vivo, transient overexpression of circulating biglycan at the onset of renal ischemia/reperfusion injury (IRI) enhanced M1 macrophage recruitment into the kidneys of Cd44 and Cd44 mice but not Cd14 mice. The biglycan-CD44 interaction increased M1 autophagy and the number of renal M2 macrophages and reduced tubular damage following IRI. Thus, CD44 is a novel signaling co-receptor for biglycan, an interaction that is required for TLR4-CD44-dependent pro-autophagic activity in macrophages. Interfering with the interaction between biglycan and specific TLR co-receptors could represent a promising therapeutic intervention to curtail kidney inflammation and damage.
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http://dx.doi.org/10.1016/j.kint.2018.10.037DOI Listing
March 2019

Analysis of Cell Type-Specific Effects of MicroRNA-92a Provides Novel Insights Into Target Regulation and Mechanism of Action.

Circulation 2018 11;138(22):2545-2558

Institute of Cardiovascular Regeneration, Goethe University, Frankfurt, Germany (E.-M.R., W.T.A., C.B., D.J., M.H.S., J.K., A.F., A.B., S.D.).

Background: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction.

Methods: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45 hematopoietic cells.

Results: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro.

Conclusions: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034598DOI Listing
November 2018

Progranulin Deficient Mice Develop Nephrogenic Diabetes Insipidus.

Aging Dis 2018 Oct 1;9(5):817-830. Epub 2018 Oct 1.

1Clinical Pharmacology, Goethe-University Hospital Frankfurt am Main, Germany.

Loss-of-function mutations of progranulin are associated with frontotemporal dementia in humans, and its deficiency in mice is a model for this disease but with normal life expectancy and mild cognitive decline on aging. The present study shows that aging progranulin deficient mice develop progressive polydipsia and polyuria under standard housing conditions starting at middle age (6-9 months). They showed high water licking behavior and doubling of the normal daily drinking volume, associated with increased daily urine output and a decrease of urine osmolality, all maintained during water restriction. Creatinine clearance, urine urea, urine albumin and glucose were normal. Hence, there were no signs of osmotic diuresis or overt renal disease, other than a concentrating defect. In line, the kidney morphology and histology revealed a 50% increase of the kidney weight, kidney enlargement, mild infiltrations of the medulla with pro-inflammatory cells, widening of tubules but no overt signs of a glomerular or tubular pathology. Plasma vasopressin levels were on average about 3-fold higher than normal levels, suggesting that the water loss resulted from unresponsiveness of the collecting tubules towards vasopressin, and indeed aquaporin-2 immunofluorescence in collecting tubules was diminished, whereas renal and hypothalamic vasopressin were increased, the latter in spite of substantial astrogliosis in the hypothalamus. The data suggest that progranulin deficiency causes nephrogenic diabetes insipidus in mice during aging. Possibly, polydipsia in affected patients - eventually interpreted as psychogenic polydipsia - may point to a similar concentrating defect.
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http://dx.doi.org/10.14336/AD.2017.1127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147595PMC
October 2018

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis.

Eur Respir J 2018 11 22;52(5). Epub 2018 Nov 22.

Dept of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany.

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.
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http://dx.doi.org/10.1183/13993003.00564-2018DOI Listing
November 2018

Factor XII in coagulation, inflammation and beyond.

Cell Signal 2018 11 15;51:257-265. Epub 2018 Aug 15.

Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Electronic address:

Factor XII (FXII) is a protease that is mainly produced in the liver and circulates in plasma as a single chain zymogen. Following contact with negatively charged surfaces, FXII is converted into the two-chain active form, FXIIa. FXIIa initiates the intrinsic blood coagulation pathway via activation of factor XI. Furthermore, it converts plasma prekallikrein to kallikrein (PK), which reciprocally activates FXII and liberates bradykinin from high molecular weight kininogen. In addition, FXIIa initiates fibrinolysis via PK-mediated urokinase activation and activates the classical complement pathway. Even though the main function of FXII seems to relate to the activation of the intrinsic coagulation pathway and the kallikrein-kinin system, a growing body of evidence suggests that FXII may also directly regulate cellular responses. In this regard, it has been found that FXII/FXIIa induces the expression of inflammatory mediators, promotes cell proliferation, and enhances the migration of neutrophils and lung fibroblasts. In addition, it has been reported that genetic ablation of FXII protects against neuroinflammation, reduces the formation of atherosclerotic lesions in Apoe mice, improves wound healing, and inhibits postnatal angiogenesis. Although the aforementioned effects can be partially explained by the downstream products of FXII activation, the ability of FXII/FXIIa to directly regulate cellular responses has recently emerged as an alternative hypothesis. These direct cellular reactions to FXII/FXIIa will be discussed in the review.
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http://dx.doi.org/10.1016/j.cellsig.2018.08.006DOI Listing
November 2018
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