scholarly journals Regulation of eosinophil functions by autophagy

2021 ◽  
Author(s):  
Nina Germic ◽  
Aref Hosseini ◽  
Shida Yousefi ◽  
Alexander Karaulov ◽  
Hans-Uwe Simon
Keyword(s):  
Immune Cell ◽  
Therapeutic Interventions ◽  
Effector Cells ◽  
Pharmacological Modulation ◽  
Atg Proteins ◽  
Physiological Relevance ◽  
Human Disorders ◽  
Intracellular Process ◽  
Cytotoxic Effector

AbstractEosinophils are granule-containing leukocytes which develop in the bone marrow. For many years, eosinophils have been recognized as cytotoxic effector cells, but recent studies suggest that they perform additional immunomodulatory and homeostatic functions. Autophagy is a conserved intracellular process which preserves cellular homeostasis. Autophagy defects have been linked to the pathogenesis of many human disorders. Evidence for abnormal regulation of autophagy, including decreased or increased expression of autophagy-related (ATG) proteins, has been reported in several eosinophilic inflammatory disorders, such as Crohn’s disease, bronchial asthma, eosinophilic esophagitis, and chronic rhinosinusitis. Despite the increasing extent of research using preclinical models of immune cell-specific autophagy deficiency, the physiological relevance of autophagic pathway in eosinophils has remained unknown until recently. Owing to the increasing evidence that eosinophils play a role in keeping organismal homeostasis, the regulation of eosinophil functions is of considerable interest. Here, we discuss the most recent advances on the role of autophagy in eosinophils, placing particular emphasis on insights obtained in mouse models of infections and malignant diseases in which autophagy has genetically dismantled in the eosinophil lineage. These studies pointed to the possibility that autophagy-deficient eosinophils exaggerate inflammation. Therefore, the pharmacological modulation of the autophagic pathway in these cells could be used for therapeutic interventions.

scholarly journals The Enigma of Eosinophil Degranulation

2021 ◽  
Vol 22 (13) ◽  
pp. 7091
Author(s):  
Timothée Fettrelet ◽  
Lea Gigon ◽  
Alexander Karaulov ◽  
Shida Yousefi ◽  
Hans-Uwe Simon
Keyword(s):  
Blood Cells ◽  
Inflammatory Diseases ◽  
White Blood Cells ◽  
Exact Role ◽  
Effector Cells ◽  
Effector Functions ◽  
Cytotoxic Effector ◽  
Eosinophil Degranulation

Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.

Human pregnancy: the role of chemokine networks at the fetal–maternal interface

2004 ◽  
Vol 6 (11) ◽  
pp. 1-14 ◽  
Author(s):  
Kristy Red-Horse ◽  
Penelope M. Drake ◽  
Susan J. Fisher
Keyword(s):  
Chemokine Receptors ◽  
Immune Cell ◽  
Leukocyte Trafficking ◽  
Placental Development ◽  
Effector Cells ◽  
Chemokine Expression ◽  
Multifunctional Molecules ◽  
And Migration ◽  
The Relationship

Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. Similar events occur in pregnancy during development of the fetal–maternal interface, where there is extensive leukocyte trafficking and tissue morphogenesis, and this is accompanied by abundant chemokine expression. The relationship between chemokines, leukocytes and placental development is beginning to be delineated. During pregnancy a specialised population of maternal leukocytes infiltrates the implantation site. These leukocytes are thought to sustain the delicate balance between protecting the developing embryo/fetus and tolerating its hemiallogeneic tissues. A network of chemokine expression by both fetal and maternal components in the pregnant uterus functions in establishing this leukocyte population. Intriguingly, experiments investigating immune cell recruitment revealed the additional possibility that chemokines influence aspects of placental development. Specifically, cytotrophoblasts, the effector cells of the placenta, express chemokine receptors that can bind ligands found at key locations, implicating chemokines as regulators of cytotrophoblast differentiation and migration. Thus, as in other systems, at the fetal–maternal interface chemokines might regulate multiple functions.

Epigenetics, Nuclear Organization & Gene Function

2019 ◽  
Author(s):  
John C. Lucchesi
Keyword(s):  
Gene Function ◽  
Genetic Regulation ◽  
Genetic Material ◽  
Three Dimensional ◽  
Therapeutic Interventions ◽  
Human Disorders ◽  
Genetic Mechanisms ◽  
Non Coding Rnas ◽  
Increased Susceptibility

Epigenetics is the study of heritable changes in gene function that do not involve changes in the DNA sequence. Epigenetic changes, consisting principally of DNA methylation, histone modifications and non-coding RNAs, maintain and modulate the initial impact of regulatory factors that recognize and associate with particular genomic sequences. This book’s primary goal is to establish a framework that can be used to understand the basis of epigenetic regulation and to appreciate both its derivation from genetics and its interdependence with genetic mechanisms. A further aim is to highlight the role played by the three-dimensional organization of the genetic material itself (the complex of DNA, histones and non-histone proteins referred to as chromatin) and its distribution within a functionally compartmentalized nucleus. Dysfunctions at any level of genetic regulation have the potential to result in an increased susceptibility to disease or actually give rise to overt pathologies. As illustrated in this book, research is continuously uncovering the role of epigenetics in a variety of human disorders, providing new avenues for therapeutic interventions and advances in regenerative medicine.

scholarly journals Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

2020 ◽  
Vol 21 (12) ◽  
pp. 4346 ◽  
Author(s):  
Anthony M. Battram ◽  
Mireia Bachiller ◽  
Beatriz Martín-Antonio
Keyword(s):  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumor Development ◽  
Cell Senescence ◽  
Therapeutic Interventions ◽  
Main Role ◽  
Suppressor Mechanism

Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.

scholarly journals Autophagy: A Friend or Foe in Allergic Asthma?

2021 ◽  
Vol 22 (12) ◽  
pp. 6314
Author(s):  
Efthymia Theofani ◽  
Georgina Xanthou
Keyword(s):  
Protective Immunity ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Building Blocks ◽  
Differentiation Antigen ◽  
Cytoplasmic Material ◽  
Human Disorders ◽  
Immune Response Regulation ◽  
Novel Therapeutic

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.

scholarly journals Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1053 ◽  
Author(s):  
Carolin Czauderna ◽  
Darko Castven ◽  
Friederike L. Mahn ◽  
Jens U. Marquardt
Keyword(s):  
Liver Cancer ◽  
Malignant Transformation ◽  
Immune Cell ◽  
Primary Liver Cancer ◽  
Dominant Role ◽  
Therapeutic Interventions ◽  
Chronic Inflammatory Cell ◽  
Therapeutic Implications ◽  
Pathway Activation

Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions.

scholarly journals Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

2020 ◽  
Vol 21 (6) ◽  
pp. 1954 ◽  
Author(s):  
Sabbir Khan ◽  
Sandeep Mittal ◽  
Kain McGee ◽  
Kristin D. Alfaro-Munoz ◽  
Nazanin Majd ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Treatment Resistance ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Myeloid Derived Suppressor Cells ◽  
Antitumor Effects ◽  
Glioma Progression

Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

scholarly journals Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Maximilian Wiendl ◽  
Emily Becker ◽  
Tanja M. Müller ◽  
Caroline J. Voskens ◽  
Markus F. Neurath ◽  
...  
Keyword(s):  
Immune Cell ◽  
Therapeutic Interventions ◽  
Cell Trafficking ◽  
Future Directions ◽  
Immune Cell Trafficking ◽  
Multifactorial Diseases ◽  
Medical Need ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.

The Critical Role of the NKG2D Receptor in CD8+CTL and CD8+CD56+ NKT Cell Cytotoxicity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3164-3164
Author(s):  
Jia-Yan Wu ◽  
John M. Hill ◽  
Marc Ernstoff ◽  
Kenneth R. Meehan
Keyword(s):  
Tumor Cells ◽  
Ex Vivo ◽  
Critical Role ◽  
Effector Cells ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Nkg2d Receptor ◽  
Cytotoxic Effector ◽  
Tumor Cell Killing

Abstract We previously demonstrated the ability to grow and ex vivo expand mobilized peripheral blood mononuclear cells (PBMNC) from myeloma patients into aggressive cytotoxic effector cells (Blood102; 422b, 2003). These experiments were designed to test the function and mechanism of tumor cell killing of these cells. Peripheral blood stem cells (PBSC) were collected from myeloma pts after mobilizing with cyclophosphamide and rhG-CSF and cultured in Aim-V serum-free medium at 37 and 5% CO2. After 2 hrs, the non-adherent cells were removed and placed in culture with Aim-V, IL-2 (50 IU/ml) and OKT-3 (50 ng/ml) for 7 days. Cytotoxicity of the expanded cells was tested on Day 0 and Day 7 using a chromium release assay. To identify the cytotoxic potential of cell subsets, cell populations were depleted using the Auto MACS Magnetic Cell Sorter (Miltenyi Biotec Auburn, CA) and cytotoxicity assays were repeated. Since the CD8+ cell(s) were the most cytotoxic, the CD8+ cells were isolated and their mechanisms of tumor cell killing were evaluated by testing killing through MHC Class I, T cell receptor or the NKG2D receptor. The ex vivo expanded population was extremely cytotoxic and killed RPMI 8226 myeloma cells at 60% lysis (+/− 1.6%) (E:T of 100:1) when compared to 3.9 % on day 0 (+/− 0.8%). CD8+ or CD8+CD56+ cell subsets contributed to > 83.3 % (+/− 1.5%) of the killing. Blocking the TCR pathway (Redirected Cytotoxicity Assay) had no effect on killing and blocking the MHC Class I molecules decreased cytotoxicity by only 6%. When the NKG2D receptor was blocked, cytotoxicity by the CD8+ cells decreased by 48% (+/− 2%), demonstrating the critical role of the NKG2D in these CD8+ cell populations. The expanded cytotoxic effector cells aggressively lyse myeloma tumor cells in a MHC and non-MHC restricted fashion. These ex vivo expanded CD8+ cells likely acquire the NKG2D receptor and kill tumor cells in a non-MHC restricted manner. Since MHC expression is often low or absent on myeloma cells and the NKG2D ligands are fairly specific to tumor cells, the infusion of these ex vivo expanded cells following transplant may improve clinical outcomes.

scholarly journals The Role of Ferroptosis-Related Gene in the Immune Activity and Prognosis of Sepsis

2022 ◽  
Author(s):  
Wei Dai ◽  
Yu Tian ◽  
Deqiang Luo ◽  
Qian Xie ◽  
Fen Liu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Cell ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
Therapeutic Interventions ◽  
Calibration Plot ◽  
Pathway Enrichment Analysis ◽  
Regulated Cell Death

IntroductionSepsis is a leading cause of mortality in intensive care units worldwide. Ferroptosis, a form of regulated cell-death–related iron, has been proven to be altered during sepsis, including increased iron transport and uptake into cells and decreased iron export. A better understanding of the role of ferroptosis in sepsis should expedite the identification of biomarkers for prognostic evaluation and therapeutic interventions.Material and methodsWe used the mRNA expression profiles of sepsis patients from Gene Expression Omnibus (GEO) to analyze the expression level of ferroptosis-related genes and construct molecular subtypes.ResultsTwo distinct ferroptosis patterns were determined, and the overall survival of the two clusters was highly significantly different. Gene comparison analysis was performed on these two groups, and there were a total of 106 differentially expressed genes(DEGs). Pathway enrichment analysis of these genes showed that ferroptosis and immune-related pathways were enriched, suggesting that immune pathways might be critically involved in sepsis. To systematically predict the prognosis of sepsis, we constructed a nomogram model, the calibration plot nomogram showed excellent concordance for the 7-, 14-, and 28-days predicted and actual overall survival probabilities. Finally, the results of bioinformatics analysis were validated in animal and cell modelsConclusionsIn this study, we construct a ferroptosis-related nomogram that can be used for prognostic prediction in sepsis. In addition, we revealed the ferroptosis played a non-negligible role in immune cell infiltration and guiding more effective immunotherapy strategies.

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