Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation

2015 ◽  
Vol 56 (1-2) ◽  
pp. 19-31 ◽  
Author(s):  
Johanna Puegge ◽  
Yongzhi Wang ◽  
Jonas Roller ◽  
Su Zhang ◽  
Lingtao Luo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cell Damage ◽  
Leukocyte Recruitment ◽  
Pharmacological Intervention ◽  
Lymphocyte Function ◽  
Leukocyte Accumulation ◽  
Histone 3 ◽  
Neutrophil Depletion

Background: Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation. Methods: Histone 3 and TNF-α were intrascrotally administered, and anti-P-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1) antibody and neutrophil depletion antibody were injected intravenously or intraperitoneally. Results: Intrascrotal injection of histone 3 dose-dependently increased leukocyte recruitment. Neutrophil depletion abolished intravascular and extravascular leukocytes after histone 3 challenge, suggesting that neutrophils were the dominating leukocyte subtype responding to histone stimulation. Pretreatment with an anti-P-selectin and an anti-PSGL-1 antibody abolished histone-stimulated neutrophil rolling, adhesion and emigration. When the anti-P-selectin or the anti-PSGL-1 antibody was administrated after histone 3 stimulation, neutrophil rolling was reduced, whereas the number of firmly adherent and emigrated neutrophils were unchanged, suggesting that the inhibitory effect of blocking P-selectin and PSGL-1 on neutrophil adhesion and recruitment was due to the reduction in neutrophil rolling. Moreover, pretreatment with antibodies against Mac-1 and LFA-1 had no effect of neutrophil rolling but abolished adhesion and emigration evoked by histone 3. Thus, our data demonstrate that P-selectin and PSGL-1 play an important role in histone-induced inflammatory cell recruitment by mediating neutrophil rolling as a precondition for histone-provoked firm adhesion and emigration in vivo. Moreover, we conclude that both Mac-1 and LFA-1 are critical in supporting histone-provoked firm adhesion of neutrophils to endothelial cells. Conclusion: These novel findings define specific selectins and integrins as potential targets for pharmacological intervention in histone-dependent inflammatory diseases.

Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo

2019 ◽  
Vol 60 (1-2) ◽  
pp. 53-62
Author(s):  
Feifei Du ◽  
Yongzhi Wang ◽  
Zhiyi Ding ◽  
Matthias W. Laschke ◽  
Henrik Thorlacius
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pharmacological Intervention ◽  
Lymphocyte Function ◽  
Microvascular Endothelium ◽  
Recruitment Methods ◽  
Leukocyte Accumulation ◽  
Tnf Α

Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.

scholarly journals Importance of Primary Capture and L-Selectin–Dependent Secondary Capture in Leukocyte Accumulation in Inflammation and Atherosclerosis in Vivo

2001 ◽  
Vol 194 (2) ◽  
pp. 205-218 ◽  
Author(s):  
Einar E. Eriksson ◽  
Xun Xie ◽  
Joachim Werr ◽  
Peter Thoren ◽  
Lennart Lindbom
Keyword(s):  
Shear Rate ◽  
Leukocyte Recruitment ◽  
Wall Shear Rate ◽  
Free Flow ◽  
Initial Contact ◽  
Atherosclerotic Lesions ◽  
Leukocyte Accumulation ◽  
Wall Shear ◽  
Rolling Leukocytes

In the multistep process of leukocyte extravasation, the mechanisms by which leukocytes establish the initial contact with the endothelium are unclear. In parallel, there is a controversy regarding the role for L-selectin in leukocyte recruitment. Here, using intravital microscopy in the mouse, we investigated leukocyte capture from the free flow directly to the endothelium (primary capture), and capture mediated through interactions with rolling leukocytes (secondary capture) in venules, in cytokine-stimulated arterial vessels, and on atherosclerotic lesions in the aorta. Capture was more prominent in arterial vessels compared with venules. In venules, the incidence of capture increased with increasing vessel diameter and wall shear rate. Secondary capture required a minimum rolling leukocyte flux and contributed by ∼20–50% of total capture in all studied vessel types. In arteries, secondary capture induced formation of clusters and strings of rolling leukocytes. Function inhibition of L-selectin blocked secondary capture and thereby decreased the flux of rolling leukocytes in arterial vessels and in large (>45 μm in diameter), but not small (<45 μm), venules. These findings demonstrate the importance of leukocyte capture from the free flow in vivo. The different impact of blockage of secondary capture in venules of distinct diameter range, rolling flux, and wall shear rate provides explanations for the controversy regarding the role of L-selectin in various situations of leukocyte recruitment. What is more, secondary capture occurs on atherosclerotic lesions, a fact that provides the first evidence for roles of L-selectin in leukocyte accumulation in atherogenesis.

scholarly journals Classification of lymphoid neoplasms: the microscope as a tool for disease discovery

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4384-4399 ◽  
Author(s):  
Elaine S. Jaffe ◽  
Nancy Lee Harris ◽  
Harald Stein ◽  
Peter G. Isaacson
Keyword(s):  
Molecular Mechanisms ◽  
Nk Cell ◽  
Clinical Manifestations ◽  
Lymphoid Cells ◽  
World Health ◽  
International Studies ◽  
Lymphocyte Function ◽  
Lymphoid Neoplasms

AbstractIn the past 50 years, we have witnessed explosive growth in the understanding of normal and neoplastic lymphoid cells. B-cell, T-cell, and natural killer (NK)–cell neoplasms in many respects recapitulate normal stages of lymphoid cell differentiation and function, so that they can be to some extent classified according to the corresponding normal stage. Likewise, the molecular mechanisms involved the pathogenesis of lymphomas and lymphoid leukemias are often based on the physiology of the lymphoid cells, capitalizing on deregulated normal physiology by harnessing the promoters of genes essential for lymphocyte function. The clinical manifestations of lymphomas likewise reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the World Health Organization (WHO) classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory.

scholarly journals miR-155 accelerates proliferation of mouse hepatocytes during liver regeneration by directly targeting SOCS1

2018 ◽  
Vol 315 (4) ◽  
pp. G443-G453 ◽  
Author(s):  
Xia Lin ◽  
Li Chen ◽  
Haiyan Li ◽  
Yu Liu ◽  
Yanhong Guan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Molecular Mechanisms ◽  
Pharmacological Intervention ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Proliferation Of Hepatocytes

Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.

Cellular and molecular mechanisms of HGF/Met in the cardiovascular system

2015 ◽  
Vol 129 (12) ◽  
pp. 1173-1193 ◽  
Author(s):  
Simona Gallo ◽  
Valentina Sala ◽  
Stefano Gatti ◽  
Tiziana Crepaldi
Keyword(s):  
Growth Factor ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Receptor ◽  
Ischaemic Injury ◽  
Protective Function

Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.

scholarly journals CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 777-785 ◽  
Author(s):  
Stefanie Kliche ◽  
Tim Worbs ◽  
Xiaoqian Wang ◽  
Janine Degen ◽  
Irene Patzak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Lymphocyte Function ◽  
Essential Components ◽  
Antigen Presenting ◽  
Inside Out

Abstract The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.

scholarly journals Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes

2003 ◽  
Vol 197 (12) ◽  
pp. 1701-1707 ◽  
Author(s):  
Petronela Ancuta ◽  
Ravi Rao ◽  
Ashlee Moses ◽  
Andrew Mehle ◽  
Sunil K. Shaw ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Monocyte Subset ◽  
Blood Monocytes ◽  
Monocyte Chemoattractant Protein 1 ◽  
Pathological Conditions ◽  
Normal Individuals ◽  
And Migration

CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.

scholarly journals Repair Injured Heart by Regulating Cardiac Regenerative Signals

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Wen-Feng Cai ◽  
Guan-Sheng Liu ◽  
Lei Wang ◽  
Christian Paul ◽  
Zhi-Li Wen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Heart Diseases ◽  
Cardiac Regeneration ◽  
Heart Tissue ◽  
Cardiomyocyte Proliferation ◽  
Proliferation Capacity ◽  
End Stage

Cardiac regeneration is a homeostatic cardiogenic process by which the sections of malfunctioning adult cardiovascular tissues are repaired and renewed employing a combination of both cardiomyogenesis and angiogenesis. Unfortunately, while high-quality regeneration can be performed in amphibians and zebrafish hearts, mammalian hearts do not respond in kind. Indeed, a long-term loss of proliferative capacity in mammalian adult cardiomyocytes in combination with dysregulated induction of tissue fibrosis impairs mammalian endogenous heart regenerative capacity, leading to deleterious cardiac remodeling at the end stage of heart failure. Interestingly, several studies have demonstrated that cardiomyocyte proliferation capacity is retained in mammals very soon after birth, and cardiac regeneration potential is correspondingly preserved in some preadolescent vertebrates after myocardial infarction. There is therefore great interest in uncovering the molecular mechanisms that may allow heart regeneration during adult stages. This review will summarize recent findings on cardiac regenerative regulatory mechanisms, especially with respect to extracellular signals and intracellular pathways that may provide novel therapeutics for heart diseases. Particularly, bothin vitroandin vivoexperimental evidences will be presented to highlight the functional role of these signaling cascades in regulating cardiomyocyte proliferation, cardiomyocyte growth, and maturation, with special emphasis on their responses to heart tissue injury.

scholarly journals Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

2019 ◽  
Author(s):  
Michelle Kokkinou ◽  
Elaine E. Irvine ◽  
David R. Bonsall ◽  
Sridhar Natesan ◽  
Lisa A. Wells ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Molecular Mechanisms ◽  
Imaging Study ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Pharmacological Intervention ◽  
Dopamine Synthesis ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

ABSTRACTPatients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5, P<0.001) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

scholarly journals Pathological Neuroinflammatory Conversion of Reactive Astrocytes Is Induced by Microglia and Involves Chromatin Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Alejandro Villarreal ◽  
Camila Vidos ◽  
Matías Monteverde Busso ◽  
María Belén Cieri ◽  
Alberto Javier Ramos
Keyword(s):  
Chromatin Remodeling ◽  
Molecular Mechanisms ◽  
Reactive Astrocytes ◽  
Pharmacological Intervention ◽  
Temporary Increase ◽  
Epigenetic Changes ◽  
Cns Injury ◽  
Gain Of Function ◽  
Pathological Remodeling

Following brain injury or in neurodegenerative diseases, astrocytes become reactive and may suffer pathological remodeling, features of which are the loss of their homeostatic functions and a pro-inflammatory gain of function that facilitates neurodegeneration. Pharmacological intervention to modulate this astroglial response and neuroinflammation is an interesting new therapeutic research strategy, but it still requires a deeper understanding of the underlying cellular and molecular mechanisms of the phenomenon. Based on the known microglial–astroglial interaction, the prominent role of the nuclear factor kappa B (NF-κB) pathway in mediating astroglial pathological pro-inflammatory gain of function, and its ability to recruit chromatin-remodeling enzymes, we first explored the microglial role in the initiation of astroglial pro-inflammatory conversion and then monitored the progression of epigenetic changes in the astrocytic chromatin. Different configurations of primary glial culture were used to modulate microglia–astrocyte crosstalk while inducing pro-inflammatory gain of function by lipopolysaccharide (LPS) exposure. In vivo, brain ischemia by cortical devascularization (pial disruption) was performed to verify the presence of epigenetic marks in reactive astrocytes. Our results showed that 1) microglia is required to initiate the pathological conversion of astrocytes by triggering the NF-κB signaling pathway; 2) this interaction is mediated by soluble factors and induces stable astroglial phenotypic changes; 3) the pathological conversion promotes chromatin remodeling with stable increase in H3K9K14ac, temporary increase in H3K27ac, and temporary reduction in heterochromatin mark H3K9me3; and 4) in vivo reactive astrocytes show increased H3K27ac mark in the neuroinflammatory milieu from the ischemic penumbra. Our findings indicate that astroglial pathological pro-inflammatory gain of function is associated with profound changes in the configuration of astrocytic chromatin, which in turn are initiated by microglia-derived cues. These results open a new avenue in the study of potential pharmacological interventions that modify the initiation and stabilization of astroglial pathological remodeling, which would be useful in acute and chronic CNS injury. Epigenetic changes represent a plausible pharmacological target to interfere with the stabilization of the pathological astroglial phenotype.

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