scholarly journals The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Antje Egners ◽  
Merve Erdem ◽  
Thorsten Cramer
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Diseases ◽  
Neutrophil Function ◽  
Proper Function ◽  
Low Oxygen ◽  
Bacterial Killing ◽  
Molecular Responses ◽  
Chronic Inflammatory Diseases ◽  
Hypoxic Conditions ◽  
Cellular Components

Lack of oxygen (hypoxia) is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF) family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.

scholarly journals Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 9041
Author(s):  
Sirsendu Jana ◽  
Michael R. Heaven ◽  
Abdu I. Alayash
Keyword(s):  
Endothelial Cells ◽  
Hypoxia Inducible Factor ◽  
Spike Protein ◽  
Receptor Interaction ◽  
Low Oxygen ◽  
Viral Receptor ◽  
Hypoxic Conditions ◽  
Viral Components ◽  
Induced Changes ◽  
The Impact

SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.

scholarly journals The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1121-1130 ◽  
Author(s):  
Silvio Danese ◽  
Stefania Vetrano ◽  
Li Zhang ◽  
Victoria A. Poplis ◽  
Francis J. Castellino
Keyword(s):  
Inflammatory Bowel Disease ◽  
Innate Immunity ◽  
Bowel Disease ◽  
Protein C ◽  
Inflammatory Diseases ◽  
Pathogenic Role ◽  
Chronic Inflammatory Diseases ◽  
Therapeutic Implications ◽  
Inflammatory Bowel ◽  
Cellular Components

Abstract Inflammation and coagulation are closely linked interdependent processes. Under physiologic conditions, the tissue microcirculation functions in anticoagulant and anti-inflammatory fashions. However, when inflammation occurs, coagulation is also set in motion and actively participates in enhancing inflammation. Recently, novel and unexpected roles of hemostasis in the humoral and cellular components of innate immunity have been described. In particular, the protein C system, besides its well-recognized role in anticoagulation, plays a crucial role in inflammation. Indeed, the protein C system is now emerging as a novel participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease, atherosclerosis, and lung and heart inflammation, and may emerge as unexpected therapeutic targets for intervention.

scholarly journals Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?

2018 ◽  
Vol 2018 ◽  
pp. 1-25 ◽  
Author(s):  
Luca Parisi ◽  
Elisabetta Gini ◽  
Denisa Baci ◽  
Marco Tremolati ◽  
Matteo Fanuli ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Cancer Type ◽  
Effector Cells ◽  
Chronic Inflammatory Diseases ◽  
Pathological Conditions ◽  
Cellular Components ◽  
Cell Cell

Macrophages are key cellular components of the innate immunity, acting as the main player in the first-line defence against the pathogens and modulating homeostatic and inflammatory responses. Plasticity is a major feature of macrophages resulting in extreme heterogeneity both in normal and in pathological conditions. Macrophages are not homogenous, and they are generally categorized into two broad but distinct subsets as either classically activated (M1) or alternatively activated (M2). However, macrophages represent a continuum of highly plastic effector cells, resembling a spectrum of diverse phenotype states. Induction of specific macrophage functions is closely related to the surrounding environment that acts as a relevant orchestrator of macrophage functions. This phenomenon, termed polarization, results from cell/cell, cell/molecule interaction, governing macrophage functionality within the hosting tissues. Here, we summarized relevant cellular and molecular mechanisms driving macrophage polarization in “distant” pathological conditions, such as cancer, type 2 diabetes, atherosclerosis, and periodontitis that share macrophage-driven inflammation as a key feature, playing their dual role as killers (M1-like) and/or builders (M2-like). We also dissect the physio/pathological consequences related to macrophage polarization within selected chronic inflammatory diseases, placing polarized macrophages as a relevant hallmark, putative biomarkers, and possible target for prevention/therapy.

scholarly journals APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling

2020 ◽  
Vol 28 (5) ◽  
pp. 1223-1235
Author(s):  
A. L. Cross ◽  
J. Hawkes ◽  
H. L. Wright ◽  
R. J. Moots ◽  
S. W. Edwards
Keyword(s):  
Inflammatory Diseases ◽  
Cell Signalling ◽  
Neutrophil Function ◽  
Receptor Expression ◽  
Bacterial Killing ◽  
Surface Receptors ◽  
Cell Functions ◽  
Inflammatory Conditions ◽  
Neutrophil Degranulation ◽  
Surface Receptor

Abstract Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10–1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.

scholarly journals Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2705-2712 ◽  
Author(s):  
Maura Calvani ◽  
Annamaria Rapisarda ◽  
Badarch Uranchimeg ◽  
Robert H. Shoemaker ◽  
Giovanni Melillo
Keyword(s):  
Endothelial Cells ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Umbilical Vein ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Low Oxygen ◽  
Autocrine Loop ◽  
Hypoxic Induction ◽  
Hypoxic Conditions

AbstractHypoxia is a major pathophysiological condition for the induction of angiogenesis, which is a crucial aspect of growth in solid tumors. In mammalian cells, the transcriptional response to oxygen deprivation is largely mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimer composed of HIF-1α and HIF-1β subunits. However, the response of endothelial cells to hypoxia and the specific involvement of HIF-α subunits in this process are still poorly understood. We show that human umbilical vein endothelial cells (HUVECs) cultured in the absence of growth factors survive and form tubelike structures when cultured under hypoxic, but not normoxic, conditions. HUVECs expressed both HIF-1α and HIF-2α when cultured under hypoxic conditions. Transfection of HIF-1α, but not HIF-2α, siRNA to HUVECs completely abrogated hypoxic induction of cords. Neutralizing antibodies to bFGF, but not IGF-1, VEGF, or PDGF-BB, blocked survival and sprouting of HUVECs under hypoxic conditions, suggesting the existence of an autocrine loop induced by low oxygen levels. Notably, bFGF-dependent induction of cord formation under normoxic conditions required HIF-1α activity, which was also essential for hypoxic induction of bFGF mRNA and protein expression. These results uncover the existence of an HIF-1α–bFGF amplification pathway that mediates survival and sprouting of endothelial cells under hypoxic conditions.

scholarly journals Single-Cell RNA Sequencing Reveals Heterogeneity and Functional Diversity of Lymphatic Endothelial Cells

2021 ◽  
Vol 22 (21) ◽  
pp. 11976
Author(s):  
Hannah den Braanker ◽  
Astrid C. van Stigt ◽  
Marc R. Kok ◽  
Erik Lubberts ◽  
Radjesh J. Bisoendial
Keyword(s):  
Immune Response ◽  
Endothelial Cells ◽  
Single Cell ◽  
Functional Diversity ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Lymphatic Endothelial Cells ◽  
Chronic Inflammatory Diseases ◽  
Single Cell Rna Sequencing ◽  
Lymphatic Vasculature

Lymphatic endothelial cells (LECs) line the lymphatic vasculature and play a central role in the immune response. LECs have abilities to regulate immune transport, to promote immune cell survival, and to cross present antigens to dendritic cells. Single-cell RNA sequencing (scRNA) technology has accelerated new discoveries in the field of lymphatic vascular biology. This review will summarize these new findings in regard to embryonic development, LEC heterogeneity with associated functional diversity, and interactions with other cells. Depending on the organ, location in the lymphatic vascular tree, and micro-environmental conditions, LECs feature unique properties and tasks. Furthermore, adjacent stromal cells need the support of LECs for fulfilling their tasks in the immune response, such as immune cell transport and antigen presentation. Although aberrant lymphatic vasculature has been observed in a number of chronic inflammatory diseases, the knowledge on LEC heterogeneity and functional diversity in these diseases is limited. Combining scRNA sequencing data with imaging and more in-depth functional experiments will advance our knowledge of LECs in health and disease. Building the case, the LEC could be put forward as a new therapeutic target in chronic inflammatory diseases, counterweighting the current immune-cell focused therapies.

Chronic Inflammatory Diseases: Progress and Prospect with Herbal Medicine

2015 ◽  
Vol 22 (2) ◽  
pp. 247-264 ◽  
Author(s):  
Nilanjan Ghosh ◽  
Asif Ali ◽  
Rituparna Ghosh ◽  
Shaileyee Das ◽  
Subhash C. Mandal ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Diseases

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

scholarly journals Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2809
Author(s):  
Paolo Uva ◽  
Maria Carla Bosco ◽  
Alessandra Eva ◽  
Massimo Conte ◽  
Alberto Garaventa ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Low Oxygen ◽  
Connectivity Map ◽  
Hypoxic Conditions ◽  
Connectivity Score

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.

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