Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19

SARS-CoV2 infection not only causes abnormal severe pneumonia but also induces other relevant pathophysiological effects on several tissues and organs. In this regard, the clinical complications observed in COVID-19 include acute coronary syndrome, pulmonary thromboembolism, myocarditis and, in the severe cases, the occurrence of disseminated intravascular coagulation. Literature on COVID-19 highlighted the central role of the Renin Angiotensin Aldosterone System in the determinism of SARS-CoV2 cellular internalization in the target tissues. Lung degeneration and respiratory distress appear to be dependent on the perturbance of physiological mechanisms, such as the uncontrolled release of pro-inflammatory cytokines, a dysregulation of the fibrinolytic coagulative cascade and the hyperactivation of immune effector cells. In this mini review, we address the physiology of Midkine, a growth factor able to bind heparin, and its pathophysiological potential role in COVID-19 determinism. Midkine increases in many inflammatory and autoimmune conditions and correlates with several dysfunctional immune-inflammatory responses that appear to show similarities with the pathophysiological elicited by SARS-CoV2. Midkine, together with its receptor, could facilitate the virus entry, fostering its accumulation and increasing its affinity with Ace2 receptor. We also focus on Netosis, a particular mechanism of pathogen clearance exerted by neutrophils, which under certain pathological condition becomes dysfunctional and can cause tissue damage. Moreover, we highlight the mechanism of autophagy that the new coronavirus could try to escape in order to replicate itself, as well as on pulmonary fibrosis induced by hypoxia and on the release of cytokines and mediators of inflammation, correlating the interplay between Midkine and SARS-CoV2.

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A Regulatory Role for Interleukin 4 in Differential Inflammatory Responses in the Lung following Infection of Mice Primed with Th1- or Th2-Inducing Pertussis Vaccines

Infection and Immunity ◽

10.1128/iai.68.3.1383-1390.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1383-1390 ◽

Cited By ~ 24

Author(s):

Peter McGuirk ◽

Kingston H. G. Mills

Keyword(s):

Inflammatory Response ◽

Inflammatory Responses ◽

Th2 Cells ◽

Infection Model ◽

Local Production ◽

Local Inflammatory Response ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

Th1 And Th2

ABSTRACT Protection against infectious pathogens at mucosal surfaces is dependent on local antibody responses, production of inflammatory mediators, and recruitment of immune effector cells to the site of infection. Since Th1 and Th2 cells produce cytokines with pro- and anti-inflammatory activities, immunization with vaccines that induce these T-cell subtypes may regulate the subsequent inflammatory response to infection. We have demonstrated that immunization of mice with pertussis whole-cell or acellular vaccines (Pw or Pa) selectively induces Th1 and Th2 cells, respectively. In this study we have used a murine respiratory-infection model to demonstrate that priming with a Th1- or Th2-inducing pertussis vaccine can influence the local inflammatory response and immune effector cells in the lung following aerosol challenge with Bordetella pertussis. Analysis of bronchoalveolar lavage (BAL) fluid taken during the course of B. pertussis infection of naı̈ve mice or mice immunized with Pw revealed an early influx of neutrophils and local production of interleukin 1β (IL-1β) in the lungs. In contrast, neutrophil infiltration and IL-1β production were not observed following challenge of mice immunized with the Th2-inducing Pa. Conversely, during infection local production of IL-6 and IL-1ra was significantly greater in mice immunized with Pa than in those immunized with Pw. Studies of knockout mice revealed neutrophil and lymphocyte infiltration in the lungs following B. pertussis infection of IL-4-defective (IL-4−/−) mice but not in wild-type mice immunized with Pa. Furthermore, the levels of IL-1β, IL-6, and IL-1ra in Pa-immunized IL-4−/− mice were comparable to those in mice immunized with Pw. These results demonstrate distinct influences of Th1- and Th2-inducing vaccines on the protective inflammatory responses in the lungs following challenge with B. pertussis and implicate IL-4 as an important regulator of inflammatory-cell recruitment.

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Role and function of macrophages in the metabolic syndrome

Biochemical Journal ◽

10.1042/bj20111708 ◽

2012 ◽

Vol 442 (2) ◽

pp. 253-262 ◽

Cited By ~ 78

Author(s):

Prerna Bhargava ◽

Chih-Hao Lee

Keyword(s):

Metabolic Syndrome ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Metabolic Stress ◽

Innate Immune ◽

Signalling Pathways ◽

Immune Effector ◽

Effector Cells ◽

The Metabolic Syndrome ◽

And Function

Macrophages are key innate immune effector cells best known for their role as professional phagocytes, which also include neutrophils and dendritic cells. Recent evidence indicates that macrophages are also key players in metabolic homoeostasis. Macrophages can be found in many tissues, where they respond to metabolic cues and produce pro- and/or anti-inflammatory mediators to modulate metabolite programmes. Certain metabolites, such as fatty acids, ceramides and cholesterol crystals, elicit inflammatory responses through pathogen-sensing signalling pathways, implicating a maladaptation of macrophages and the innate immune system to elevated metabolic stress associated with overnutrition in modern societies. The outcome of this maladaptation is a feedforward inflammatory response leading to a state of unresolved inflammation and a collection of metabolic pathologies, including insulin resistance, fatty liver, atherosclerosis and dyslipidaemia. The present review summarizes what is known about the contributions of macrophages to metabolic diseases and the signalling pathways that are involved in metabolic stress-induced macrophage activation. Understanding the role of macrophages in these processes will help us to develop therapies against detrimental effects of the metabolic syndrome.

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Macrophages—the immune effector guardians of the lung: impact of corticosteroids on their functional responses

Clinical Science ◽

10.1042/cs20200382 ◽

2020 ◽

Vol 134 (13) ◽

pp. 1631-1635

Author(s):

Stephan F. van Eeden ◽

Kentaro Akata

Keyword(s):

Functional Properties ◽

Inflammatory Responses ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Chronic Obstructive ◽

Macrophage Phenotype ◽

Functional Responses ◽

Immune Effector ◽

Effector Cells ◽

The Impact

Abstract Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs’ effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.

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Immune Response of Human Polymorphnuclear Neutrophils to Aspergillus Fumigatus

Blood ◽

10.1182/blood.v112.11.1257.1257 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1257-1257

Author(s):

Juergen Loeffler ◽

Iwona Wozniok ◽

Markus Mezger ◽

Hermann Einsele

Keyword(s):

Gene Expression ◽

Aspergillus Fumigatus ◽

Fungal Pathogens ◽

Inflammatory Responses ◽

Fungal Infections ◽

Polymorphonuclear Neutrophils ◽

Clinical Strain ◽

Immune Effector ◽

Effector Cells ◽

Human Pmns

Abstract Invasive fungal infections with Aspergillus fumigatus show an increasing incidence due to the growing number of severely immunocompromised patients. Polymorphonuclear neutrophils (PMNs), as part of the innate immune system, are key players in antifungal immune responses, recognizing fungal pathogens at an early step of infection. Besides phagocytic mechanisms, PMNs kill pathogens by the release of reactive oxygen species (ROS). Human PMNs were isolated from blood of healthy donors using Biocoll separation. Cells were co-cultivated with conidia, germlings and hyphae of the clinical strain ATCC 9197. The oxidative burst was determined in a kinetic measurement quantifying dichlorfluorescein production. Chemotaxis was analyzed by transwell assays. Furthermore, total RNA was extracted and gene expression profiling was performed using Affymetrix U133Plus2.0 arrays. We could demonstrate that A. fumigatus represents a strong stimulus releasing ROS, depending on the morphotype; germlings revealed high ROS release, whereas resting conidia showed low stimulation capacity. PMNs actively tracked germlings and directly attached to fungi as demonstrated by real-time microscopy. Transwell assays revealed that chemotaxis of PMN is strongly dependent on the fungal morphotype; PMN showed only weak chemotaxis in the presence of conidia, whereas in the presence of germlings, high chemotactic activity was achieved. Furthermore, after 6h co-cultivation of PMNs and A. fumigatus germ tubes, 195 (1.273) genes showed an at least 4fold (2fold) altered gene expression. We observed upregulation of genes (hemoxygenase, heat shock 70kDa protein, HSPA8, HSPA1B, HSP90AB1, Ferritin) involved in self-protection against radicals. Additionally, genes involved in inflammatory responses (IL-8, CCL3, CXCL2, IL1RN) were significantly upregulated. Luminex analysis was performed for TNF-a, IL-12, GM-CSF, IFN-γ, IL-6, IL-8, IL-10 and IL-1b to identify secreted cytokines, thereby confirming array data. In conclusion, A. fumigatus had substantial effects on the activation of human PMNs. Various defence strategies were initiated, including phagocytosis, ROS release and mobilization of other immune effector cells by secretion of chemoattractants.

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Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽

10.1038/s41388-021-01846-x ◽

2021 ◽

Author(s):

Audrey Lequeux ◽

Muhammad Zaeem Noman ◽

Malina Xiao ◽

Kris Van Moer ◽

Meriem Hasmim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Transcriptional Activity ◽

Immune Cell ◽

Tumor Resistance ◽

Combination Strategy ◽

Immune Effector ◽

Effector Cells ◽

Melanoma Patients ◽

The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

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The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases

Nutrients ◽

10.3390/nu13041318 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1318

Author(s):

Tarek Benameur ◽

Raffaella Soleti ◽

Chiara Porro

Keyword(s):

Inflammatory Responses ◽

Pathological Condition ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

In Vivo Studies ◽

Innovative Drug ◽

Chronic Neuroinflammation

Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.

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The Role of Microglia in Sporadic Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201248 ◽

2021 ◽

Vol 79 (3) ◽

pp. 961-968

Author(s):

Wolfgang J. Streit ◽

Habibeh Khoshbouei ◽

Ingo Bechmann

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Genetic Mutations ◽

Sporadic Alzheimer’S Disease ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

Amyloid Cascade

Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

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Next-generation cell therapies: the emerging role of CAR-NK cells

Hematology ◽

10.1182/hematology.2020002547 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 570-578

Author(s):

Rafet Basar ◽

May Daher ◽

Katayoun Rezvani

Keyword(s):

T Cells ◽

Cell Therapy ◽

Natural Killer ◽

Γδ T Cells ◽

Antigen Receptors ◽

T Cell Therapy ◽

Cell Therapies ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Abstract T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.

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Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma

Journal of Neurosurgery ◽

10.3171/2009.11.jns09901 ◽

2010 ◽

Vol 113 (2) ◽

pp. 280-285 ◽

Cited By ~ 18

Author(s):

James Miller ◽

Guenter Eisele ◽

Ghazaleh Tabatabai ◽

Steffen Aulwurm ◽

Gabriele von Kürthy ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Malignant Gliomas ◽

Ectopic Expression ◽

Glioma Cells ◽

Interferon Γ ◽

Soluble Form ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.

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Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD)

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2005.1701 ◽

2005 ◽

Vol 360 (1461) ◽

pp. 1747-1767 ◽

Cited By ~ 42

Author(s):

Bruce R Blazar ◽

William J Murphy

Keyword(s):

Graft Versus Host Disease ◽

Opportunistic Infections ◽

Haematopoietic Stem Cell ◽

Generation Process ◽

Host Disease ◽

Immune Effector ◽

Effector Cells ◽

Graft Versus Host ◽

Donor T Cells ◽

Donor Graft

Haematopoietic stem cell transplantation (HSCT) offers promise for the treatment of haematological and immune disorders, solid tumours, and as a tolerance inducing regimen for organ transplantation. Allogeneic HSCTs engraftment requires immunosuppression and the anti-tumour effects are dependent upon the immune effector cells that are contained within or generated from the donor graft. However, significant toxicities currently limit its efficacy. These problems include: (i) graft-versus-host disease (GVHD) in which donor T cells attack the recipient resulting in multi-organ attack and morbidity, (ii) a profound period of immune deficiency following HSCT, and (iii) donor graft rejection. Currently available methods to prevent or treat GVHD with systemic immunosuppression can lead to impaired immune recovery, increased opportunistic infections, and higher relapse rates. This review will provide an overview of GVHD pathophysiology and discuss the roles of various cells, pathways, and factors in the GVHD generation process and in the preservation of graft-versus-tumour effects. Variables that need to be taken into consideration in attempting to extrapolate preclinical results to the clinical paradigm will be highlighted.

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