Neutrophil activation via β2 integrins (CD11/CD18): Molecular mechanisms and clinical implications

2007 ◽  
Vol 98 (08) ◽  
pp. 262-273 ◽  
Author(s):  
Jürgen Schymeinsky ◽  
Attila Mócsai ◽  
Barbara Walzog
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Acute Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Polymorphonuclear Neutrophils ◽  
Downstream Signaling ◽  
Β2 Integrin ◽  
Pmn Functions ◽  
Integrin Family ◽  
Β2 Integrins

SummaryPolymorphonuclear neutrophils (PMN) are key components of the innate immunity and their efficient recruitment to the sites of lesion is a prerequisite for acute inflammation. Signaling via adhesion molecules of the β2 integrin family (CD11/CD18) plays an essential role for PMN recruitment and activation during inflammation. In this review, we will focus on the non-receptor tyrosine kinase Syk, an important downstream signaling component of β2 integrins that is required for the control of different PMN functions including adhesion,migration and phagocytosis. The exploration of β2 integrin-mediated Syk activation provided not only novel insights into the control of PMN functions but also led to the identification of Syk as a new molecular target for therapeutic intervention during inflammatory diseases.

scholarly journals Regulators and Effectors of Arf GTPases in Neutrophils

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Jouda Gamara ◽  
François Chouinard ◽  
Lynn Davis ◽  
Fawzi Aoudjit ◽  
Sylvain G. Bourgoin
Keyword(s):  
Molecular Mechanisms ◽  
Proteolytic Enzymes ◽  
Leading Edge ◽  
Cell Polarization ◽  
Polymorphonuclear Neutrophils ◽  
Cellular Events ◽  
Gtpase Activating Proteins ◽  
Nadph Oxidase Complex ◽  
Pmn Functions ◽  
Phagosomal Membrane

Polymorphonuclear neutrophils (PMNs) are key innate immune cells that represent the first line of defence against infection. They are the first leukocytes to migrate from the blood to injured or infected sites. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of migrating PMNs. These phagocytes actively engulf microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens with bactericidal compounds. Association of the NADPH oxidase complex at the phagosomal membrane for production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. G protein-dependent signalling pathways tightly control PMN functions. In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses. GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells. The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology.

scholarly journals LDL-receptor–related protein regulates β2-integrin–mediated leukocyte adhesion

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 170-177 ◽  
Author(s):  
Patricia P. E. M. Spijkers ◽  
Paula da Costa Martins ◽  
Erik Westein ◽  
Carl G. Gahmberg ◽  
Jaap J. Zwaginga ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Leukocyte Adhesion ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
U937 Cells ◽  
Related Protein ◽  
Β2 Integrin ◽  
Adhesive Surface ◽  
Β2 Integrins

Abstract β2-Integrin clustering on activation is a key event in leukocyte adhesion to the endothelium during the inflammatory response. In the search for molecular mechanisms leading to this clustering, we have identified low-density lipoprotein (LDL) receptor–related protein (LRP) as a new partner for β2-integrins at the leukocyte surface. Immobilized recombinant LRP fragments served as an adhesive surface for blood-derived leukocytes and the U937 cell line. This adhesion was decreased up to 95% in the presence of antibodies against β2-integrins, pointing to these integrins as potential partners for LRP. Using purified proteins, LRP indeed associated with the αMβ2 complex and the αM and αL I-domains (Kd, app ≈ 0.5 μM). Immunoprecipitation experiments and confocal microscopy revealed that endogenously expressed LRP and αLβ2 colocalized in monocytes and U937 cells. Furthermore, activation of U937 cells resulted in clustering of αLβ2 and LRP to similar regions at the cell surface, indicating potential cooperation between both proteins. This was confirmed by the lack of αLβ2 clustering in U937 cells treated by antisense oligonucleotides to down-regulate LRP. In addition, the absence of LRP resulted in complete abrogation of β2-integrin–dependent adhesion to endothelial cells in a perfusion system, demonstrating the presence of a previously unrecognized link between LRP and leukocyte function.

scholarly journals Anti-inflammatory effects of polymethoxyflavones from citrus peels: a review

2018 ◽  
Vol 3 ◽  
pp. 76-86 ◽  
Author(s):  
Xiaoqi Wang ◽  
Shiming Li ◽  
Chia-Cheng Wei ◽  
Junqing Huang ◽  
Min-Hsiung Pan ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Acute Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Stress Reactions ◽  
Citrus Peel ◽  
Immune Stress ◽  
Body Tissues ◽  
Citrus Peels

Inflammation is a non-specific kind of biological immune response of body tissues to any type of external or internal injuries, such as pathogens, irritants and immune stress reactions. There are two types of inflammation, namely acute and chronic. Acute inflammation starts and develops rapidly, and is aroused by various factors, including injuries, infection, toxins or immune reactions. Chronic inflammation usually lasts for an extended long period of time and results from elimination failure of acute inflammation, autoimmune disorders, various pathogens and pathogenic environments. Except for the damage itself, there exists a direct and intimate connection between chronic inflammation and various clinic common diseases, such as neurodegeneration, as well as metabolic and cardiovascular ailments. Citrus peel is a by-product generated in citrus juice processing. Polymethoxyflavones (PMFs) exist abundantly and almost exclusively in citrus peels, and their biological activities have been broadly investigated in recent years. PMFs have proven to possess potential inhibitory bioactivities towards a number of functional and immune diseases including inflammation. The two most abundant PMFs exhibiting prominent bioactivities in citrus peels are nobiletin and tangeretin, ubiquitously detected in various citrus species. In this review, the beneficial health effects and the underlying molecular mechanisms of ten main citrus PMFs were illustrated against numerous inflammatory diseases, including inflammatory bowel disease (IBD), neuroinflammation and organ inflammation, among others.

scholarly journals Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2101-2111 ◽  
Author(s):  
Chad E. Green ◽  
Ulrich Y. Schaff ◽  
Melissa R. Sarantos ◽  
Aaron F. H. Lum ◽  
Donald E. Staunton ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Major Axis ◽  
Flow Chamber ◽  
Cell Polarization ◽  
Parallel Plate Flow Chamber ◽  
Β2 Integrin ◽  
High Affinity ◽  
Molecule Inhibitor ◽  
Inflamed Endothelium ◽  
Β2 Integrins

Polymorphonuclear leukocyte (PMN) recruitment to vascular endothelium during acute inflammation involves cooperation between selectins, G-proteins, and β2-integrins. LFA-1 (CD11a/CD18) affinity correlates with specific adhesion functions because a shift from low to intermediate affinity supports rolling on ICAM-1, whereas high affinity is associated with shear-resistant leukocyte arrest. We imaged PMN adhesion on cytokine-inflamed endothelium in a parallel-plate flow chamber to define the dynamics of β2-integrin function during recruitment and transmigration. After arrest on inflamed endothelium, high-affinity LFA-1 aligned along the uropod-pseudopod major axis, which was essential for efficient neutrophil polarization and subsequent transmigration. An allosteric small molecule inhibitor targeted to the I-domain stabilized LFA-1 in an intermediate-affinity conformation, which supported neutrophil rolling but inhibited cell polarization and abrogated transmigration. We conclude that a shift in LFA-1 from intermediate to high affinity during the transition from rolling to arrest provides the contact-mediated signaling and guidance necessary for PMN transmigration on inflamed endothelium.

scholarly journals RTX Toxins Ambush Immunity’s First Cellular Responders

Toxins ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 720 ◽  
Author(s):  
Laura C. Ristow ◽  
Rodney A. Welch
Keyword(s):  
Cell Receptor ◽  
Uropathogenic Escherichia Coli ◽  
Beta Subunit ◽  
Critical Question ◽  
Β2 Integrin ◽  
Host Cell Receptor ◽  
Rtx Toxins ◽  
Single Host ◽  
Integrin Family ◽  
Β2 Integrins

The repeats-in-toxin (RTX) family represents a unique class of bacterial exoproteins. The first family members described were toxins from Gram-negative bacterial pathogens; however, additional members included exoproteins with diverse functions. Our review focuses on well-characterized RTX family toxins from Aggregatibacter actinomycetemcomitans (LtxA), Mannheimia haemolytica (LktA), Bordetella pertussis (CyaA), uropathogenic Escherichia coli (HlyA), and Actinobacillus pleuropneumoniae (ApxIIIA), as well as the studies that have honed in on a single host cell receptor for RTX toxin interactions, the β2 integrins. The β2 integrin family is composed of heterodimeric members with four unique alpha subunits and a single beta subunit. β2 integrins are only found on leukocytes, including neutrophils and monocytes, the first responders to inflammation following bacterial infection. The LtxA, LktA, HlyA, and ApxIIIA toxins target the shared beta subunit, thereby targeting all types of leukocytes. Specific β2 integrin family domains are required for the RTX toxin’s cytotoxic activity and are summarized here. Research examining the domains of the RTX toxins required for cytotoxic and hemolytic activity is also summarized. RTX toxins attack and kill phagocytic immune cells expressing a single integrin family, providing an obvious advantage to the pathogen. The critical question that remains, can the specificity of the RTX-β2 integrin interaction be therapeutically targeted?

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Zhang ◽  
Christopher D. Kontos ◽  
Brian H. Annex ◽  
Aleksander S. Popel
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Reaction Network ◽  
Vascular Growth ◽  
Downstream Signaling ◽  
Signaling Axis ◽  
Agonistic Activity ◽  
Molecular Regulatory Mechanisms

AbstractThe Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

Sign in / Sign up

Export Citation Format

Share Document