12 results on '"Grisaru-Tal S"'
Search Results
2. CD300b regulates intestinal inflammation and promotes repair in colitis.
- Author
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Avlas S, Kassis H, Itan M, Reichman H, Dolitzky A, Hazut I, Grisaru-Tal S, Gordon Y, Tsarfaty I, Karo-Atar D, Rozenberg P, Bitton A, and Munitz A
- Subjects
- Humans, Mice, Animals, Intestinal Mucosa, Inflammation metabolism, Colitis chemically induced, Colitis genetics, Inflammatory Bowel Diseases metabolism
- Abstract
Chronic inflammation is a hallmark charataristic of various inflammatory diseases including inflammatory bowel disease. Subsequently, current therapeutic approaches target immune-mediated pathways as means for therapeutic intervention and promotion of mucosal healing and repair. Emerging data demonstrate important roles for CD300 receptor family members in settings of innate immunity as well as in allergic and autoimmune diseases. One of the main pathways mediating the activities of CD300 family members is via promotion of resolution through interactions with ligands expressed by viruses, bacteria, or dead cells (e.g., phospholipids such as PtdSer and/or ceramide). We have recently shown that the expression of CD300a, CD300b and CD300f were elevated in patients with IBD and that CD300f (but not CD300a) regulates colonic inflammation in response to dextran sodium sulphate (DSS)-induced colitis. Whether CD300b has a role in colitis or mucosal healing is largely unknown. Herein, we demonstrate a central and distinct role for CD300b in colonic inflammation and subsequent repair. We show that Cd300b
-/- mice display defects in mucosal healing upon cessation of DSS treatment. Cd300b-/- mice display increased weight loss and disease activity index, which is accompanied by increased colonic histopathology, increased infiltration of inflammatory cells and expression of multiple pro-inflammatory upon cessation of DSS cytokines. Furthermore, we demonstrate that soluble CD300b (sCD300b) is increased in the colons of DSS-treated mice and establish that CD300b can bind mouse and human epithelial cells. Finally, we show that CD300b decreases epithelial EpCAM expression, promotes epithelial cell motility and wound healing. These data highlight a key role for CD300b in colonic inflammation and repair processes and suggest that CD300b may be a future therapeutic target in inflammatory GI diseases., Competing Interests: Author AM is a consultant for Electra-TAU, Glaxo Smith Kline, Astra Zeneca, Sanofi, Oravax, Sartorious, Chemomab and is an inventor of patents owned by the Tel Aviv University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Avlas, Kassis, Itan, Reichman, Dolitzky, Hazut, Grisaru-Tal, Gordon, Tsarfaty, Karo-Atar, Rozenberg, Bitton and Munitz.)- Published
- 2023
- Full Text
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3. Epithelial cell-expressed type II IL-4 receptor mediates eosinophilic esophagitis.
- Author
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Avlas S, Shani G, Rhone N, Itan M, Dolitzky A, Hazut I, Grisaru-Tal S, Gordon Y, Shoda T, Ballaban A, Ben-Baruch NM, Rochman M, Diesendruck Y, Nahary L, Bitton A, Halpern Z, Benhar I, Varol C, Rothenberg ME, and Munitz A
- Subjects
- Humans, Mice, Animals, Interleukin-13 Receptor alpha1 Subunit metabolism, Interleukin-4 genetics, Interleukin-4 metabolism, Interleukin-13 metabolism, Epithelial Cells metabolism, Eosinophilic Esophagitis pathology
- Abstract
Background: Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease, characterized by eosinophil-rich inflammation in the esophagus. The histopathological and clinical features of EoE have been attributed to overproduction of the type 2 cytokines IL-4 and IL-13, which mediate profound alterations in the esophageal epithelium and neutralizing of their shared receptor component (IL-4Rα) with a human antibody drug (dupilumab) demonstrates clinical efficacy. Yet, the relative contribution of IL-4 and IL-13 and whether the type II IL-4 receptor (comprised of the IL-4Rα chain in association with IL-13Rα1) mediates this effect has not been determined., Methods: Experimental EoE was induced in WT, Il13ra1
-/- , and Krt14Cre /Il13ra1fl/fl mice by skin-sensitized using 4-ethoxymethylene-2-phenyl-2-oxazolin (OXA) followed by intraesophageal challenges. Esophageal histopathology was determined histologically. RNA was extracted and sequenced for transcriptome analysis and compared with human EoE RNAseq data., Results: Induction of experimental EoE in mice lacking Il13ra1 and in vivo IL-13 antibody-based neutralization experiments blocked antigen-induced esophageal epithelial and lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo targeted deletion of Il13ra1 in esophageal epithelial cells rendered mice protected from experimental EoE. Single-cell RNA sequencing analysis of human EoE biopsies revealed predominant expression of IL-13Rα1 in epithelial cells and that EoE signature genes correlated with IL-13 expression compared with IL-4., Conclusions: We demonstrate a definitive role for IL-13 signaling via IL-13Rα1 in EoE. These data provide mechanistic insights into the mode of action of current therapies in EoE and highlight the type II IL-4R as a future therapeutic target., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)- Published
- 2023
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4. T cell-eosinophil crosstalk-A new road for effective immune checkpoint blockade in breast cancer?
- Author
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Grisaru-Tal S and Munitz A
- Subjects
- Humans, Female, Immune Checkpoint Inhibitors therapeutic use, T-Lymphocytes, Eosinophils, Breast Neoplasms therapy
- Abstract
Immune checkpoint blockade (ICB) has revolutionized the landscape of cancer treatment. Nevertheless, most cancer patients still do not respond to ICB. In this issue of Cancer Cell, Blomberg et al. illustrate a critical cooperation between T cells and eosinophils, which jointly enhance effectiveness of ICB in breast cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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5. Differential regulation of Type 1 and Type 2 mouse eosinophil activation by apoptotic cells.
- Author
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Dolitzky A, Hazut I, Avlas S, Grisaru-Tal S, Itan M, Zaffran I, Levi-Schaffer F, Gerlic M, and Munitz A
- Subjects
- Mice, Animals, Cytokines metabolism, Interferon-gamma metabolism, Apoptosis, Eosinophils metabolism, Escherichia coli metabolism
- Abstract
Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis, host defense and cancer. Although eosinophils have been studied mostly in the context of Type 2 inflammatory responses, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Notably, both Type 1- and Type 2 inflammatory environments are characterized by tissue damage and cell death. Collectively, this raises the possibility that eosinophils can interact with apoptotic cells, which can alter eosinophil activation in the inflammatory milieu. Herein, we demonstrate that eosinophils can bind and engulf apoptotic cells. We further show that exposure of eosinophils to apoptotic cells induces marked transcriptional changes in eosinophils, which polarize eosinophils towards an anti-inflammatory phenotype that is associated with wound healing and cell migration. Using an unbiased RNA sequencing approach, we demonstrate that apoptotic cells suppress the inflammatory responses of eosinophils that were activated with IFN-γ + E. coli (e.g., Type 1 eosinophils) and augment IL-4-induced eosinophil activation (e.g., Type 2 eosinophils). These data contribute to the growing understanding regarding the heterogeneity of eosinophil activation patterns and highlight apoptotic cells as potential regulators of eosinophil polarization., Competing Interests: AM is a consultant for Glaxo Smith Kline, Astra Zeneca, Sanofi, Oravax, Sartorious and is an inventor of three patents owned by the Tel Aviv University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor YT declared a shared parent affiliation with the authors IZ and F-LS at the time of review., (Copyright © 2022 Dolitzky, Hazut, Avlas, Grisaru-Tal, Itan, Zaffran, Levi-Schaffer, Gerlic and Munitz.)
- Published
- 2022
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6. Mouse resident lung eosinophils are dependent on IL-5.
- Author
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Dolitzky A, Grisaru-Tal S, Avlas S, Hazut I, Gordon Y, Itan M, and Munitz A
- Subjects
- Animals, Antigens, Differentiation, Myelomonocytic, Leukocyte Count, Lung, Mice, Eosinophils, Interleukin-5
- Published
- 2022
- Full Text
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7. Eosinophil-lymphocyte interactions in the tumor microenvironment and cancer immunotherapy.
- Author
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Grisaru-Tal S, Rothenberg ME, and Munitz A
- Subjects
- Eosinophils, Humans, Immune Checkpoint Inhibitors, Immunity, Innate, Immunotherapy, Killer Cells, Natural pathology, Neoplasms, Tumor Microenvironment
- Abstract
Eosinophils are important effector cells and therapeutic targets in allergic diseases. Emerging data indicate that eosinophils infiltrate a variety of solid tumor types and have pleiotropic activities by at least two non-mutually exclusive mechanisms: direct interactions with tumor cells, and intricate cross-talk with lymphocytes. In light of the immune checkpoint inhibition revolution in cancer therapy, we review eosinophil-lymphocyte interactions in the tumor microenvironment. We also analyze potential interactions between eosinophils and lymphocyte subsets, including T cells, natural killer cells and innate lymphoid cells. We provide perspectives on the consequences of these interactions and how eosinophils are accessory cells that can affect the response to various forms of T cell-mediated immunotherapies and might be therapeutically targeted to improve cancer immunotherapy., (© 2022. Springer Nature America, Inc.)
- Published
- 2022
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8. Transcriptional Profiling of Mouse Eosinophils Identifies Distinct Gene Signatures Following Cellular Activation.
- Author
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Dolitzky A, Shapira G, Grisaru-Tal S, Hazut I, Avlas S, Gordon Y, Itan M, Shomron N, and Munitz A
- Subjects
- Animals, Biomarkers, Cell Plasticity genetics, Cell Plasticity immunology, Computational Biology methods, Cytokines genetics, Cytokines metabolism, Escherichia coli immunology, Gene Expression Profiling, Gene Ontology, High-Throughput Nucleotide Sequencing, Immune System Phenomena, Immunity, Inflammation Mediators, Lipopolysaccharides immunology, Macrophages immunology, Macrophages metabolism, Mice, Eosinophils immunology, Eosinophils metabolism, Gene Expression Regulation, Transcriptome
- Abstract
Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis to host defense and cancer. Eosinophils have been studied mostly in the context of Type 2 inflammatory responses such as those found in allergy. Nonetheless, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Recent data suggest that the pleotropic roles of eosinophils are due to heterogeneous responses to environmental cues. Despite this, the activation profile of eosinophils, in response to various stimuli is yet to be defined. To better understand the transcriptional spectrum of eosinophil activation, we exposed eosinophils to Type 1 (e.g. IFN-γ, E. coli ) vs. Type 2 (e.g. IL-4) conditions and subjected them to global RNA sequencing. Our analyses show that IL-4, IFN-γ, E. coli and IFN-γ in the presence of E. coli (IFN-γ/ E. coli )-stimulated eosinophils acquire distinct transcriptional profiles, which polarize them towards what we termed Type 1 and Type 2 eosinophils. Bioinformatics analyses using Gene Ontology based on biological processes revealed that different stimuli induced distinct pathways in eosinophils. These pathways were confirmed using functional assays by assessing cytokine/chemokine release (i.e. CXCL9, CCL24, TNF-α and IL-6) from eosinophils following activation. In addition, analysis of cell surface markers highlighted CD101 and CD274 as potential cell surface markers that distinguish between Type 1 and Type 2 eosinophils, respectively. Finally, the transcriptome signature of Type 1 eosinophils resembled that of eosinophils that were obtained from mice with experimental colitis whereas the transcriptome signature of Type 2 eosinophils resembled that of eosinophils from experimental asthma. Our data demonstrate that eosinophils are polarized to distinct "Type 1" and "Type 2" phenotypes following distinct stimulations. These findings provide fundamental knowledge regarding the heterogeneity of eosinophils and support the presence of transcriptional differences between Type 1 and Type 2 cells that are likely reflected by their pleotropic activities in diverse disease settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dolitzky, Shapira, Grisaru-Tal, Hazut, Avlas, Gordon, Itan, Shomron and Munitz.)
- Published
- 2021
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9. Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity.
- Author
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Grisaru-Tal S, Dulberg S, Beck L, Zhang C, Itan M, Hediyeh-Zadeh S, Caldwell J, Rozenberg P, Dolitzky A, Avlas S, Hazut I, Gordon Y, Shani O, Tsuriel S, Gerlic M, Erez N, Jacquelot N, Belz GT, Rothenberg ME, Davis MJ, Yu H, Geiger T, Madi A, and Munitz A
- Subjects
- Animals, Apoptosis, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation, Female, Humans, Lung Neoplasms metabolism, Lung Neoplasms secondary, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms immunology, CD8-Positive T-Lymphocytes immunology, Eosinophils immunology, Lung Neoplasms immunology, Receptors, CCR3 physiology, Tumor Microenvironment
- Abstract
The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein-coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ-activated eosinophils facilitated CD4
+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. SIGNIFICANCE: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
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10. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.
- Author
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Jacquelot N, Seillet C, Wang M, Pizzolla A, Liao Y, Hediyeh-Zadeh S, Grisaru-Tal S, Louis C, Huang Q, Schreuder J, Souza-Fonseca-Guimaraes F, de Graaf CA, Thia K, Macdonald S, Camilleri M, Luong K, Zhang S, Chopin M, Molden-Hauer T, Nutt SL, Umansky V, Ciric B, Groom JR, Foster PS, Hansbro PM, McKenzie ANJ, Gray DHD, Behren A, Cebon J, Vivier E, Wicks IP, Trapani JA, Munitz A, Davis MJ, Shi W, Neeson PJ, and Belz GT
- Subjects
- Animals, Cell Line, Tumor, Chemotaxis, Leukocyte drug effects, Cytotoxicity, Immunologic drug effects, Eosinophils drug effects, Eosinophils immunology, Eosinophils metabolism, Female, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Humans, Lymphocytes immunology, Lymphocytes metabolism, Male, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Skin Neoplasms genetics, Skin Neoplasms immunology, Skin Neoplasms metabolism, Mice, Antibodies pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Immune Checkpoint Inhibitors pharmacology, Interleukin-33 pharmacology, Lymphocytes drug effects, Melanoma, Experimental drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Skin Neoplasms drug therapy
- Abstract
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
- Published
- 2021
- Full Text
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11. Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations.
- Author
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Grisaru-Tal S, Itan M, Grass DG, Torres-Roca J, Eschrich SA, Gordon Y, Dolitzky A, Hazut I, Avlas S, Jacobsen EA, Ziv-Baran T, and Munitz A
- Subjects
- Eosinophils, Female, Humans, Leukocyte Count, Mucous Membrane, Tumor Microenvironment, Eosinophilia, Neoplasms
- Abstract
Eosinophils are bone marrow-derived granulocytes that display key effector functions in allergic diseases. Nonetheless, recent data highlight important roles for eosinophils in the tumor microenvironment (TME). Eosinophils have been attributed with pleiotropic and perhaps conflicting functions, which may be attributed at least in part to variations in eosinophil quantitation in the TME. Thus, a reliable, quantitative, and robust method for the assessment of eosinophilic infiltration in the TME is required. This type of methodology could standardize the identification of these cells and promote the subsequent generation of hypothesis-driven mechanistic studies. To this end, we conducted a comprehensive analysis of multiple primary tumors from distinct anatomical sites using a standardized method. Bioinformatics analysis of 10,469 genomically profiled primary tumors revealed that eosinophil abundance within different tumors can be categorized into three groups representing tumors with high, intermediate, and low eosinophil levels. Consequently, eosinophil abundance, as well as spatial distribution, was determined in tissue tumor arrays of six tumors representing all three classifications (colon and esophagus - high; lung - intermediate; cervix, ovary, and breast - low). With the exception of breast cancer, eosinophils were mainly localized in the tumor stroma. Importantly, the tumor anatomical site was identified as the primary predictive factor of eosinophil stromal density highlighting a distinction between mucosal-barrier organs versus non-mucosal barrier organs. These findings enhance our understanding of eosinophil diversity in the TME and provide a compelling rationale for future experiments assessing the activity of these cells., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2020
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12. A new dawn for eosinophils in the tumour microenvironment.
- Author
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Grisaru-Tal S, Itan M, Klion AD, and Munitz A
- Subjects
- Animals, Biomarkers, Chemotaxis, Leukocyte genetics, Chemotaxis, Leukocyte immunology, Combined Modality Therapy, Disease Management, Disease Susceptibility, Eosinophils immunology, Eosinophils metabolism, Gene Expression Regulation, Neoplastic, Humans, Neoplasms etiology, Neoplasms metabolism, Neoplasms therapy, Signal Transduction, Eosinophils pathology, Neoplasms pathology, Tumor Microenvironment genetics, Tumor Microenvironment immunology
- Abstract
Eosinophils are evolutionarily conserved, pleotropic cells that display key effector functions in allergic diseases, such as asthma. Nonetheless, eosinophils infiltrate multiple tumours and are equipped to regulate tumour progression either directly by interacting with tumour cells or indirectly by shaping the tumour microenvironment (TME). Eosinophils can readily respond to diverse stimuli and are capable of synthesizing and secreting a large range of molecules, including unique granule proteins that can potentially kill tumour cells. Alternatively, they can secrete pro-angiogenic and matrix-remodelling soluble mediators that could promote tumour growth. Herein, we aim to comprehensively outline basic eosinophil biology that is directly related to their activity in the TME. We discuss the mechanisms of eosinophil homing to the TME and examine their diverse pro-tumorigenic and antitumorigenic functions. Finally, we present emerging data regarding eosinophils as predictive biomarkers and effector cells in immunotherapy, especially in response to immune checkpoint blockade therapy, and highlight outstanding questions for future basic and clinical cancer research.
- Published
- 2020
- Full Text
- View/download PDF
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