Abstract 336: Interleukin 4 and 13 Signaling in Myeloid Cells Regulates Cardiac Regeneration

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Santiago Alvarez ◽  
Samantha Paddock ◽  
Caitlin Omeara
Keyword(s):  
Immune Cell ◽  
Myeloid Cells ◽  
Cardiac Regeneration ◽  
Mannose Receptor ◽  
The United States ◽  
Interleukin 4 ◽  
Current Therapy ◽  
Specific Cell ◽  
Cardiomyocyte Proliferation ◽  
Arginase 1

Introduction: Heart failure is a very important disease in the United States and worldwide, with a projected prevalence of 8 million by 2030. Current therapy partially decreases progression; however, mortality continues to be high, and progression to terminal HF is still significant, requiring heart transplant and other interventions that further increase morbidity and overall disease burden and costs. Therefore, the need to develop new therapies that target HF progression. Our prior work and published studies demonstrate that IL13 promotes cardiac regeneration, however, the mechanism mediating this response is currently unknown. IL13 and IL4 share a common receptor, and both cytokines are known to polarize macrophages into a pro-reparative phenotype. Here, we hypothesize that IL4/13 signaling in myeloid cells promotes heart regeneration after cardiac injury. Methods and Results: We compared cardiac regeneration in IL4Ra null/FLOXed (IL4Rα-/fl) and IL4Rα-/fl lysosome M Cre littermate mice, knocking out IL4Rα in myeloid cells. We performed apical resection on postnatal day 1 (P1) mice and assessed cardiac regeneration by histological analysis. We found that mice lacking IL4Ra in myeloid cells (IL4rafl/-, LysMCre) had significantly impaired cardiac regenerative capacity compared to Cre negative littermate controls. We also performed gene expression analysis by qPCR in whole hearts collected at 2dpi to quantify macrophages markers. Cre positive mice trended higher for expression of arginase 1 and mannose receptor 1 (p=0.055 and 0.057, respectively; student t-test) compared to Cre negative littermates. Conclusions and Discussion: Lack of IL4/13 signaling in myeloid cells impairs cardiac regeneration after injury in neonatal mice and modulated expression of immune markers. To confirm these results, flow cytometry to quantify immune cell infiltration can be performed. Other components that limit damage extension can also be assessed, like angiogenesis and cardiomyocyte proliferation. Our data suggest that IL4/IL13 signaling polarizes myeloid cells to a pro-reparative state in the neonatal heart. Additional studies are required to delineate the specific cell population mediating this response.

scholarly journals FUCCI-based live imaging platform reveals cell cycle dynamics and identifies pro-proliferative compounds in human iPSC-derived cardiomyocytes

2021 ◽  
Author(s):  
Francesca Murganti ◽  
Wouter Derks ◽  
Marion Baniol ◽  
Irina Simonova ◽  
Katrin Neumann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Regeneration ◽  
Indicator System ◽  
Specific Cell ◽  
Cardiomyocyte Proliferation ◽  
Compound Screening ◽  
Cell Cycle Dynamics

One of the major goals in cardiac regeneration research is to replace lost ventricular tissue with new cardiomyocytes. However, cardiomyocyte proliferation drops to low levels in neonatal hearts and is no longer efficient in compensating for the loss of functional myocardium in heart disease. We generated a human induced pluripotent stem cell (iPSC)-derived cardiomyocyte-specific cell cycle indicator system (TNNT2-FUCCI) to characterize regular and aberrant cardiomyocyte cycle dynamics. We visualized cell cycle progression in TNNT2-FUCCI and found G2 cycle arrest in endoreplicating cardiomyocytes. Moreover, we devised a live-cell compound screening platform to identify pro-proliferative drug candidates. We found that the alpha-adrenergic receptor agonist clonidine induced cardiomyocyte proliferation in vitro and increased cardiomyocyte cell cycle entry in neonatal mice. In conclusion, the TNNT2-FUCCI system is a valuable tool to characterize cardiomyocyte cell cycle dynamics and identify pro-proliferative candidates with regenerative potential in the mammalian heart.

scholarly journals Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3816
Author(s):  
Loryn Holokai ◽  
Jayati Chakrabarti ◽  
Joanne Lundy ◽  
Daniel Croagh ◽  
Pritha Adhikary ◽  
...  
Keyword(s):  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Checkpoint Inhibition ◽  
Arginase 1 ◽  
Programmed Death

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method: Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results: Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions: Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.

scholarly journals Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas

2010 ◽  
Vol 54 (6) ◽  
pp. 2437-2447 ◽  
Author(s):  
David J. Feola ◽  
Beth A. Garvy ◽  
Theodore J. Cory ◽  
Susan E. Birket ◽  
Heather Hoy ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Pulmonary Inflammation ◽  
Mannose Receptor ◽  
Lung Parenchyma ◽  
Macrophage Phenotype ◽  
Arginase 1 ◽  
Alternatively Activated

ABSTRACT Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b+ monocytes and CD4+ T cells that infiltrated the alveolar compartment. A predominant subset of CD11b+ cells was Gr-1 positive (Gr-1+), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.

scholarly journals Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Shih-Lei Lai ◽  
Rubén Marín-Juez ◽  
Pedro Luís Moura ◽  
Carsten Kuenne ◽  
Jason Kuan Han Lai ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cell Dynamics ◽  
Macrophage Recruitment ◽  
Ability To Regenerate ◽  
Scar Resolution ◽  
Molecular Bases

Zebrafish display a distinct ability to regenerate their heart following injury. However, this ability is not shared by another teleost, the medaka. In order to identify cellular and molecular bases for this difference, we performed comparative transcriptomic analyses following cardiac cryoinjury. This comparison points to major differences in immune cell dynamics between these models. Upon closer examination, we observed delayed and reduced macrophage recruitment in medaka, along with delayed neutrophil clearance. To investigate the role of immune responses in cardiac regeneration, we delayed macrophage recruitment in zebrafish and observed compromised neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. In contrast, stimulating Toll-like receptor signaling in medaka enhanced immune cell dynamics and promoted neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair.

scholarly journals A Bibliometric and Visualized Analysis of Cardiac Regeneration Over a 20-Year Period

2021 ◽  
Vol 8 ◽  
Author(s):  
Siyuan Ma ◽  
Junyu Yan ◽  
Lu Chen ◽  
Yingqi Zhu ◽  
Kaitong Chen ◽  
...  
Keyword(s):  
Web Of Science ◽  
Cardiac Regeneration ◽  
The United States ◽  
Harvard University ◽  
Cardiomyocyte Proliferation ◽  
Comprehensive Understanding ◽  
Microsoft Excel ◽  
Increasing Trend ◽  
Flow Map ◽  
First And Second Generation

Background: Recent research has suggested that cardiac regeneration may have the widely applicable potential of treating heart failure (HF). A comprehensive understanding of the development status of this field is conducive to its development. However, no bibliometric analysis has summarized this field properly. We aimed to analyze cardiac regeneration-related literature over 20 years and provide valuable insights.Methods: Publications were collected from the Web of Science Core Collection (WoSCC). Microsoft Excel, VOSviewer, CiteSpace, and alluvial generator were used to analyze and present the data.Results: The collected 11,700 publications showed an annually increasing trend. The United States and Harvard University were the leading force among all the countries and institutions. The majority of articles were published in Circulation Research, and Circulation was the most co-cited journal. According to co-citation analysis, burst detection and alluvial flow map, cardiomyocyte proliferation, stem cells, such as first-and second-generation, extracellular vesicles especially exosomes, direct cardiac reprogramming, macrophages, microRNAs, and inflammation have become more and more popular recently.Conclusions: Cardiac regeneration remains a research hotspot and develops rapidly. How to modify cardiac regeneration endogenously and exogenously may still be the hotspot in the future and should be discussed more deeply.

scholarly journals Cardiac regeneration: epicardial mediated repair

2015 ◽  
Vol 282 (1821) ◽  
pp. 20152147 ◽  
Author(s):  
Teresa Kennedy-Lydon ◽  
Nadia Rosenthal
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Cardiac Fibroblasts ◽  
Cardiac Regeneration ◽  
Repair Process ◽  
Regenerative Process ◽  
Cardiac Stem Cell ◽  
Cardiomyocyte Proliferation ◽  
Lower Vertebrates

The hearts of lower vertebrates such as fish and salamanders display scarless regeneration following injury, although this feature is lost in adult mammals. The remarkable capacity of the neonatal mammalian heart to regenerate suggests that the underlying machinery required for the regenerative process is evolutionarily retained. Recent studies highlight the epicardial covering of the heart as an important source of the signalling factors required for the repair process. The developing epicardium is also a major source of cardiac fibroblasts, smooth muscle, endothelial cells and stem cells. Here, we examine animal models that are capable of scarless regeneration, the role of the epicardium as a source of cells, signalling mechanisms implicated in the regenerative process and how these mechanisms influence cardiomyocyte proliferation. We also discuss recent advances in cardiac stem cell research and potential therapeutic targets arising from these studies.

705 Anti-tumor activity of CB-668, a potent, selective and orally bioavailable small-molecule inhibitor of the immuno-suppressive enzyme Interleukin 4 (IL-4)-Induced Gene 1 (IL4I1)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A747-A747
Author(s):  
Andrew MacKinnon ◽  
Deepthi Bhupathi ◽  
Jason Chen ◽  
Tony Huang ◽  
Weiqun Li ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Interleukin 4 ◽  
Mouse Tumor ◽  
Syngeneic Mouse ◽  
Molecule Inhibitor ◽  
Anti Tumor Activity ◽  
Mouse Tumor Models

BackgroundTumors evade destruction by the immune system through multiple mechanisms including altering metabolism in the tumor microenvironment. Metabolic control of immune responses occurs through depletion of essential nutrients or accumulation of toxic metabolites that impair immune cell function and promote tumor growth. The secreted enzyme interleukin 4 (IL-4)-induced gene 1 (IL4I1) is an L-phenylalanine oxidase that catabolizes phenylalanine and produces phenyl-pyruvate and hydrogen peroxide. IL4I1 regulates several aspects of adaptive immunity in mice, including inhibition of cytotoxic T cells through its production of hydrogen peroxide (reviewed in1). In human tumors, IL4I1 expression is significantly elevated relative to normal tissues and is notably high in ovarian tumors and B cell lymphomas. Motivated by the hypothesis that IL4I1 is an immuno-metabolic enzyme that suppresses anti-tumor immunity, we discovered CB-668, the first known small-molecule inhibitor of IL4I1.MethodsIL4I1 enzymatic activity was measured using an HRP-coupled enzyme assay. RNA in-situ hybridization was carried out on the RNAScope platform. Syngeneic mouse tumor models were used to evaluate the anti-tumor activity of CB-668. The level of phenyl-pyruvate in tumor homogenates was measured by LC/MS.ResultsOur clinical candidate, CB-668 is a potent and selective non-competitive inhibitor of IL4I1 (IC50 = 15 nM). CB-668 has favorable in vitro ADME properties and showed low clearance and high oral bioavailability in rodents. Twice-daily oral administration of CB-668 was well-tolerated in mice and resulted in single-agent anti-tumor activity in the syngeneic mouse tumor models B16-F10, A20, and EG7. Oral CB-668 administration reduced the levels of phenyl-pyruvate in the tumor, consistent with inhibition of IL4I1 enzymatic activity. Anti-tumor activity of CB-668 was immune cell-mediated since efficacy was abrogated in CD8-depleted mice, and CB-668 treatment caused increased expression of pro-inflammatory immune genes in the tumor. Moreover, CB-668 had no direct anti-proliferative activity on tumor cells grown in vitro (IC50 > 50 µM). CB-668 also favorably combined with anti-PD-L1 therapy to reduce tumor growth in the B16-F10 tumor model.ConclusionsThese data support an immune-mediated anti-tumor effect of IL4I1 inhibition by CB-668, and suggest inhibition of IL4I1 represents a novel strategy for cancer immuno-therapy.ReferencesMolinier-Frenkel V, Prévost-Blondel A, and Castellano F. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells 2019;8:1–9.

scholarly journals Immunometabolic Status of COVID-19 Cancer Patients

2020 ◽  
Vol 100 (4) ◽  
pp. 1839-1850
Author(s):  
A. Sica ◽  
M. P. Colombo ◽  
A. Trama ◽  
L. Horn ◽  
M. C. Garassino ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Macrophage Activation ◽  
Viral Infections ◽  
Immune Cell ◽  
Case Series ◽  
The United States ◽  
Alternative Activation ◽  
Nad Metabolism ◽  
Increased Risk

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.

scholarly journals Interleukin-4 Regulates the Expression of CD209 and Subsequent Uptake of Mycobacterium leprae by Schwann Cells in Human Leprosy

2010 ◽  
Vol 78 (11) ◽  
pp. 4634-4643 ◽  
Author(s):  
Rosane M. B. Teles ◽  
Stephan R. Krutzik ◽  
Maria T. Ochoa ◽  
Rosane B. Oliveira ◽  
Euzenir N. Sarno ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Primary Cultures ◽  
Mycobacterium Leprae ◽  
Microbial Pathogens ◽  
Interleukin 4 ◽  
Common Mechanism ◽  
Specific Cell

ABSTRACT The ability of microbial pathogens to target specific cell types is a key aspect of the pathogenesis of infectious disease. Mycobacterium leprae, by infecting Schwann cells, contributes to nerve injury in patients with leprosy. Here, we investigated mechanisms of host-pathogen interaction in the peripheral nerve lesions of leprosy. We found that the expression of the C-type lectin, CD209, known to be expressed on tissue macrophages and to mediate the uptake of M. leprae, was present on Schwann cells, colocalizing with the Schwann cell marker, CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase), along with the M. leprae antigen PGL-1 in the peripheral nerve biopsy specimens. In vitro, human CD209-positive Schwann cells, both from primary cultures and a long-term line, have a higher binding of M. leprae compared to CD209-negative Schwann cells. Interleukin-4, known to be expressed in skin lesions from multibacillary patients, increased CD209 expression on human Schwann cells and subsequent Schwann cell binding to M. leprae, whereas Th1 cytokines did not induce CD209 expression on these cells. Therefore, the regulated expression of CD209 represents a common mechanism by which Schwann cells and macrophages bind and take up M. leprae, contributing to the pathogenesis of leprosy.

Allergic Rhinitis

1992 ◽  
Vol 13 (9) ◽  
pp. 323-328
Author(s):  
Frank S. Virant
Keyword(s):  
Allergic Rhinitis ◽  
Clinical Signs ◽  
Upper Airway ◽  
Allergic Patient ◽  
The United States ◽  
Specific Ige ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Primary Defect ◽  
Primary Focus

Epidemiology Allergic rhinitis affects as many as 8% to 10% of children in the United States. Many of these children suffer significant morbidity, leading to millions of lost school days annually. Morbidity is amplified when these children concurrently suffer from complications of allergic rhinitis, such as recurrent otitis media or chronic sinus disease. Typically, children who have allergic rhinitis have a family history of atopic disorders. Upper airway allergy may become manifest at any age, but the appearance of symptoms is most common during childhood or young adulthood. Clinical signs of rhinitis may be perennial, seasonal, or episodic, and the primary focus of complaints may relate to secondary problems, including ear, sinus, or lung disease. Pathophysiology In the allergic patient, disease is mediated by the production of antigenspecific IgE by the patient's B lymphocytes. Current research suggests that the primary defect may be the excessive production of interleukin 4 (IL-4) or a deficient level of gamma interferon (γ-INF) when a T-cell is presented with an antigen. This constellation of immunomodulators directs the B-cell to produce IgE rather than the IgG response of the non-allergic patient. Clinical disease occurs when an allergen reacts with antigen-specific IgE on the patient's nasal mast cells. When these factors combine, the mast cell is activated to release a variety of preformed and newly produced mediators, including histamine, leukotrienes, and prostaglandins (Fig 1).

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