scholarly journals Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

2021 ◽  
Vol 8 ◽  
Author(s):  
Jordan R. Yaron ◽  
Liqiang Zhang ◽  
Qiuyun Guo ◽  
Shelley E. Haydel ◽  
Alexandra R. Lucas
Keyword(s):  
Immune Response ◽  
Serine Protease ◽  
Serine Proteases ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
The Body ◽  
Vascular Tree ◽  
Regulatory Pathways ◽  
Endothelial Cell Surface

The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, “off-the-shelf” system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are theserineproteaseinhibitors, termedserpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a “respiratory” coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals Systems-level immunomonitoring from acute to recovery phase of severe COVID-19

2020 ◽  
Author(s):  
Lucie Rodriguez ◽  
Pirkka Pekkarinen ◽  
Tadepally Lakshmikanth ◽  
Ziyang Tan ◽  
Camila Rosat Consiglio ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Recovery Phase ◽  
Sudden Onset ◽  
The Many ◽  
Humoral Responses ◽  
Disease Stages ◽  
Cell Cell

SUMMARYThe immune response to SARS-CoV2 is under intense investigation, but not fully understood att this moment. Severe disease is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome, rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Systems-level analyses are required to simultaneously capture all immune cell populations and the many protein mediators by which cells communicate. Since every patient analyzed will be captured at different stages of his or her infection, longitudinal monitoring of the immune response is critical. Here we report on a systems-level blood immunomonitoring study of 39 adult patients, hospitalized with severe COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ – Eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.HIGHLIGHTSSystems-level immunomonitoring from acute to recovery in severe COVID-19An IFNγ - Eosinophil axis involved in lung hyperinflammationCell-cell coregulation differ during four disease stagesBasophils and hyperinflammation modulate humoral responsesA shared trajectory of immunological recovery in severe COVID-19

Immune and Inflammatory Responses to Stroke: Good Or Bad?

2008 ◽  
Vol 3 (4) ◽  
pp. 254-265 ◽  
Author(s):  
P. A. McCombe ◽  
S. J. Read
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Regulatory Lymphocytes ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Inflammatory and immune responses play important roles following ischaemic stroke. Inflammatory responses contribute to damage and also contribute to repair. Injury to tissue triggers an immune response. This is initiated through activation of the innate immune system. In stroke there is microglial activation. This is followed by an influx of lymphocytes and macrophages into the brain, triggered by production of pro-inflammatory cytokines. This inflammatory response contributes to further tissue injury. There is also a systemic immune response to stroke, and there is a degree of immunosuppression that may contribute to the stroke patient's risk of infection. This immunosuppressive response may also be protective, with regulatory lymphocytes producing cytokines and growth factors that are neuroprotective. The specific targets of the immune response after stroke are not known, and the details of the immune and inflammatory responses are only partly understood. The role of inflammation and immune responses after stroke is twofold. The immune system may contribute to damage after stroke, but may also contribute to repair processes. The possibility that some of the immune response after stroke may be neuroprotective is exciting and suggests that deliberate enhancement of these responses may be a therapeutic option.

scholarly journals Interactions between Host Immunity and Skin-Colonizing Staphylococci: No Two Siblings Are Alike

2019 ◽  
Vol 20 (3) ◽  
pp. 718 ◽  
Author(s):  
Young Joon Park ◽  
Chae Won Kim ◽  
Heung Kyu Lee
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Bacterial Species ◽  
Host Immunity ◽  
The Body ◽  
Skin Microbiome ◽  
Staphylococcus Epidermis ◽  
Skin Commensals

As the outermost layer of the body, the skin harbors innumerable and varied microorganisms. These microorganisms interact with the host, and these interactions contribute to host immunity. One of the most abundant genera of skin commensals is Staphylococcus. Bacteria belonging to this genus are some of the most influential commensals that reside on the skin. For example, colonization by Staphylococcus aureus, a well-known pathogen, increases inflammatory responses within the skin. Conversely, colonization by Staphylococcus epidermis, a coagulase-negative staphylococcal species that are prevalent throughout the skin, can be innocuous or beneficial. Thus, manipulating the abundance of these two bacterial species likely alters the skin microbiome and modulates the cutaneous immune response, with potential implications for various inflammation-associated skin diseases. Importantly, before researchers can begin manipulating the skin microbiome to prevent and treat disease, they must first fully understand how these two species can modulate the cutaneous immune response. In this review, we discuss the nature of the interactions between these two bacterial species and immune cells within the skin, discussing their immunogenicity within the context of skin disorders.

Some antiphospholipid antibodies bind to various serine proteases in hemostasis and tip the balance toward hypercoagulant states

Lupus ◽  
2010 ◽  
Vol 19 (4) ◽  
pp. 365-369 ◽  
Author(s):  
PP Chen ◽  
M. Wu ◽  
BH Hahn
Keyword(s):  
Serine Protease ◽  
Antiphospholipid Antibodies ◽  
Serine Proteases ◽  
Blood Circulation ◽  
Conformational Epitope ◽  
The Body ◽  
Glycoprotein I ◽  
Major Antigen ◽  
New Perspective ◽  
Hemostasis Factors

The body has an elaborate system that maintains blood circulation and rapidly stops bleeding when vessels are damaged. Abnormalities that disrupt this balance may lead to thrombosis. While β2-glycoprotein I is generally accepted as the major antigen for antiphospholipid antibodies in the antiphospholipid syndrome, our accumulated studies show that some antiphospholipid antibodies bind homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Functionally, some of the protease-reactive antiphospholipid antibodies hinder anticoagulant regulation and resolution of clots, thus tip the balance toward thrombosis. Intriguingly, several serine protease-reactive antiphospholipid antibodies also react with β2-glycoprotein I, and interactions between antiphospholipid antibodies and antigens are cross-inhibited, indicating that these antiphospholipid antibodies recognize conformational epitope(s) on β2-glycoprotein I and target serine proteases. Viewed as a whole, these results extend previous reports that antiphospholipid antibodies bind to various hemostasis factors, and provide a new perspective about some antiphospholipid antibodies in terms of their binding specificities and related functional properties in promoting thrombosis.

scholarly journals Hypoxia/HIF Modulates Immune Responses

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 260
Author(s):  
Yuling Chen ◽  
Timo Gaber
Keyword(s):  
Immune Response ◽  
Cancer Progression ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Oxygen Availability ◽  
The Body ◽  
Low Oxygen ◽  
Adaptive Immune

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

scholarly journals Extravascular CX3CR1+Cells Extend Intravascular Dendritic Processes into Intact Central Nervous System Vessel Lumen

2013 ◽  
Vol 19 (4) ◽  
pp. 778-790 ◽  
Author(s):  
Deborah S. Barkauskas ◽  
Teresa A. Evans ◽  
Jay Myers ◽  
Agne Petrosiute ◽  
Jerry Silver ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Laser Scanning ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Critical Role ◽  
Laser Scanning Microscopy ◽  
Direct Access

AbstractWithin the central nervous system (CNS), antigen-presenting cells (APCs) play a critical role in orchestrating inflammatory responses where they present CNS-derived antigens to immune cells that are recruited from the circulation to the cerebrospinal fluid, parenchyma, and perivascular space. Available data indicate that APCs do so indirectly from outside of CNS vessels without direct access to luminal contents. Here, we applied high-resolution, dynamic intravital two-photon laser scanning microscopy to directly visualize extravascular CX3CR1+APC behavior deep within undisrupted CNS tissues in two distinct anatomical sites under three different inflammatory stimuli. Surprisingly, we observed that CNS-resident APCs dynamically extend their cellular processes across an intact vessel wall into the vascular lumen with preservation of vessel integrity. While only a small number of APCs displayed intravascular extensions in intact, noninflamed vessels in the brain and the spinal cord, the frequency of projections increased over days in an experimental autoimmune encephalomyelitis model, whereas the number of projections remained stable compared to baseline days after tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma. Our observation of this unique behavior by parenchyma CX3CR1+cells in the CNS argues for further exploration into their functional role in antigen sampling and immune cell recruitment.

scholarly journals Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2021 ◽  
Author(s):  
María Aguilar-Ballester ◽  
Andrea Herrero-Cervera ◽  
Ángela Vinué ◽  
Sergio Martínez-Hervás ◽  
Herminia González-Navarro
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
The Body ◽  
Cholesterol Homeostasis ◽  
Hematopoietic Stem ◽  
Regulatory Pathways ◽  
Cholesterol Levels ◽  
Atherosclerosis Development

Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.

scholarly journals A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoliang Wang ◽  
Damjan Avsec ◽  
Aleš Obreza ◽  
Shida Yousefi ◽  
Irena Mlinarič-Raščan ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Serine Protease ◽  
Serine Proteases ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophil Elastase ◽  
Fas Receptor ◽  
Gm Csf

Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)—mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) – primed neutrophils. The signaling events of this necroptotic pathway, however, remain to be investigated. In the present study, we report the design, synthesis, and characterization of a series of novel serine protease inhibitors. Two of these inhibitors, compounds 1 and 3, were able to block CD44-triggered necroptosis in GM-CSF-primed neutrophils. Both inhibitors prevented the activation of MLKL, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3’—kinase (PI3K), hence blocking the increased levels of reactive oxygen species (ROS) required for cell death. Although compounds one and three partially inhibited isolated human neutrophil elastase (HNE) activity, we obtained no pharmacological evidence that HNE is involved in the initiation of this death pathway within a cellular context. Interestingly, neither serine protease inhibitor had any effect on FAS receptor-mediated apoptosis. Taken together, these results suggest that a serine protease is involved in non-apoptotic CD44-triggered RIPK3-MLKL-dependent neutrophil cell death, but not FAS receptor-mediated caspase-dependent apoptosis. Thus, a pharmacological block on serine proteases might be beneficial for preventing exacerbation of disease in neutrophilic inflammatory responses.

scholarly journals Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by Tocilizumab

2020 ◽  
Author(s):  
Chuang Guo ◽  
Bin Li ◽  
Huan Ma ◽  
Xiaofang Wang ◽  
Pengfei Cai ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Cell ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Immunosuppressive Drug ◽  
Therapeutic Effects ◽  
Cell Analysis ◽  
Severe Stage

ABSTRACTDespite the current devastation of the COVID-19 pandemic, several recent studies have suggested that the immunosuppressive drug Tocilizumab can powerfully treating inflammatory responses that occur in this disease. Here, by employing single-cell analysis of the immune cell composition of severe-stage COVID-19 patients and these same patients in post Tocilizumab-treatment remission, we have identified a monocyte subpopulation specific to severe disease that contributes to inflammatory storms in COVID-19 patients. Although Tocilizumab treatment attenuated the strong inflammatory immune response, we found that immune cells including plasma B cells and CD8+ T cells still exhibited an intense humoral and cell-mediated anti-virus immune response in COVID-19 patients after Tocilizumab treatment. Thus, in addition to providing a rich, very high-resolution data resource about the immune cell distribution at multiple stages of the COVID-19 disease, our work both helps explain Tocilizumab’s powerful therapeutic effects and defines a large number of potential new drug targets related to inflammatory storms.

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