International Journal of Molecular Sciences

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27 pages, 4354 KiB

Open AccessArticle

Potent CCR3 Receptor Antagonist, SB328437, Suppresses Colonic Eosinophil Chemotaxis and Inflammation in the Winnie Murine Model of Spontaneous Chronic Colitis

by Rhiannon T. Filippone, Narges Dargahi, Rajaraman Eri, Jose A. Uranga, Joel C. Bornstein, Vasso Apostolopoulos and Kulmira Nurgali

Int. J. Mol. Sci. 2022, 23(14), 7780; https://doi.org/10.3390/ijms23147780 - 14 Jul 2022

Cited by 7 | Viewed by 2788

Abstract

Eosinophils and their regulatory molecules have been associated with chronic intestinal inflammation and gastrointestinal dysfunctions; eosinophil accumulation in the gut is prominent in inflammatory bowel disease (IBD). The chemokine receptor CCR3 plays a pivotal role in local and systemic recruitment and activation of [...] Read more.

Eosinophils and their regulatory molecules have been associated with chronic intestinal inflammation and gastrointestinal dysfunctions; eosinophil accumulation in the gut is prominent in inflammatory bowel disease (IBD). The chemokine receptor CCR3 plays a pivotal role in local and systemic recruitment and activation of eosinophils. In this study, we targeted CCR3-ligand interactions with a potent CCR3 receptor antagonist, SB328437, to alleviate eosinophil-associated immunological responses in the Winnie model of spontaneous chronic colitis. Winnie and C57BL/6 mice were treated with SB328437 or vehicle. Clinical and histopathological parameters of chronic colitis were assessed. Flow cytometry was performed to discern changes in colonic, splenic, circulatory, and bone marrow-derived leukocytes. Changes to the serum levels of eosinophil-associated chemokines and cytokines were measured using BioPlex. Inhibition of CCR3 receptors with SB328437 attenuated disease activity and gross morphological damage to the inflamed intestines and reduced eosinophils and their regulatory molecules in the inflamed colon and circulation. SB328437 had no effect on eosinophils and their progenitor cells in the spleen and bone marrow. This study demonstrates that targeting eosinophils via the CCR3 axis has anti-inflammatory effects in the inflamed intestine, and also contributes to understanding the role of eosinophils as potential end-point targets for IBD treatment. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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20 pages, 2894 KiB

Open AccessArticle

CCAAT/Enhancer-Binding Protein ε²⁷ Antagonism of GATA-1 Transcriptional Activity in the Eosinophil Is Mediated by a Unique N-Terminal Repression Domain, Is Independent of Sumoylation and Does Not Require DNA Binding

by Monika J. Stankiewicz, Jian Du, Dominick Martinico and Steven J. Ackerman

Int. J. Mol. Sci. 2021, 22(23), 12689; https://doi.org/10.3390/ijms222312689 - 24 Nov 2021

Cited by 2 | Viewed by 1782

Abstract

CCAAT/enhancer binding protein epsilon (C/EBPε) is required for eosinophil differentiation, lineage-specific gene transcription, and expression of C/EBPε³² and shorter 27kD and 14kD isoforms is developmentally regulated during this process. We previously defined the 27kD isoform (C/EBPε²⁷) as an antagonist of [...] Read more.

CCAAT/enhancer binding protein epsilon (C/EBPε) is required for eosinophil differentiation, lineage-specific gene transcription, and expression of C/EBPε³² and shorter 27kD and 14kD isoforms is developmentally regulated during this process. We previously defined the 27kD isoform (C/EBPε²⁷) as an antagonist of GATA-1 transactivation of the eosinophil’s major basic protein-1 (MBP1) P2-promoter, showing C/EBPε²⁷ and GATA-1 physically interact. In the current study, we used a Tat-C/EBPε²⁷ fusion protein for cell/nuclear transduction of an eosinophil myelocyte cell line to demonstrate that C/EBPε²⁷ is a potent repressor of MBP1 transcription. We performed structure-function analyses of C/EBPε²⁷ mapping its repressor domains, comparing it to C/EBPε³² and C/EBPε¹⁴, using GATA-1 co-transactivation of the MBP1-P2 promoter. Results show C/EBPε²⁷ repression of GATA-1 is mediated by its unique 68aa N-terminus combined with previously identified RDI domain. This repressor activity does not require, but is enhanced by, DNA binding via the basic region of C/EBPε²⁷ but independent of sumoylation of the RDI core “VKEEP” sumoylation site. These findings identify the N-terminus of C/EBPε²⁷ as the minimum repressor domain required for antagonism of GATA-1 in the eosinophil. C/EBPε²⁷ repression of GATA-1 occurs via a combination of both C/EBPε²⁷-GATA-1 protein–protein interaction and C/EBPε²⁷ binding to a C/EBP site in the MBP1 promoter. The C/EBPε²⁷ isoform may serve to titrate and/or turn off eosinophil granule protein genes like MBP1 during eosinophil differentiation, as these genes are ultimately silenced in the mature cell. Understanding the functionality of C/EBPε²⁷ in eosinophil development may prove promising in developing therapeutics that reduce eosinophil proliferation in allergic diseases. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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16 pages, 3524 KiB

Open AccessArticle

Transcriptional Regulation of the Human IL5RA Gene through Alternative Promoter Usage during Eosinophil Development

by Kimberly G. Laffey, Jian Du, Adam G. Schrum and Steven J. Ackerman

Int. J. Mol. Sci. 2021, 22(19), 10245; https://doi.org/10.3390/ijms221910245 - 23 Sep 2021

Cited by 3 | Viewed by 2006

Abstract

Regulation of the IL-5 receptor alpha (IL5RA) gene is complicated, with two known promoters (P1 and P2) driving transcription, and two known isoforms (transmembrane and soluble) dichotomously affecting the signaling potential of the protein products. Here, we sought to determine the [...] Read more.

Regulation of the IL-5 receptor alpha (IL5RA) gene is complicated, with two known promoters (P1 and P2) driving transcription, and two known isoforms (transmembrane and soluble) dichotomously affecting the signaling potential of the protein products. Here, we sought to determine the patterns of P1 and P2 promoter usage and transcription factor occupancy during primary human eosinophil development from CD34⁺ hematopoietic stem cell progenitors. We found that during eosinophilopoiesis, both promoters were active but subject to distinct temporal regulation, coincident with combinatorial interactions of transcription factors, including GATA-1, PU.1, and C/EBP family members. P1 displayed a relatively constant level of activity throughout eosinophil development, while P2 activity peaked early and waned thereafter. The soluble IL-5Rα mRNA peaked early and showed the greatest magnitude fold-induction, while the signaling-competent transmembrane isoform peaked moderately. Two human eosinophilic cell lines whose relative use of P1 and P2 were similar to eosinophils differentiated in culture were used to functionally test putative transcription factor binding sites. Transcription factor occupancy was then validated in primary cultures by ChIP. We conclude that IL-5-dependent generation of eosinophils from CD34⁺ precursors involves complex and dynamic activity including both promoters, several interacting transcription factors, and both signaling and antagonistic protein products. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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Review

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14 pages, 1160 KiB

Open AccessReview

Eosinophils and Lung Cancer: From Bench to Bedside

by Anne Sibille, Jean-Louis Corhay, Renaud Louis, Vincent Ninane, Guy Jerusalem and Bernard Duysinx

Int. J. Mol. Sci. 2022, 23(9), 5066; https://doi.org/10.3390/ijms23095066 - 3 May 2022

Cited by 17 | Viewed by 4251

Abstract

Eosinophils are rare, multifunctional granulocytes. Their growth, survival, and tissue migration mainly depend on interleukin (IL)-5 in physiological conditions and on IL-5 and IL-33 in inflammatory conditions. Preclinical evidence supports an immunological role for eosinophils as innate immune cells and as agents of [...] Read more.

Eosinophils are rare, multifunctional granulocytes. Their growth, survival, and tissue migration mainly depend on interleukin (IL)-5 in physiological conditions and on IL-5 and IL-33 in inflammatory conditions. Preclinical evidence supports an immunological role for eosinophils as innate immune cells and as agents of the adaptive immune response. In addition to these data, several reports show a link between the outcomes of patients treated with immune checkpoint inhibitors (ICI) for advanced cancers and blood eosinophilia. In this review, we present, in the context of non-small cell lung cancer (NSCLC), the biological properties of eosinophils and their roles in homeostatic and pathological conditions, with a focus on their pro- and anti-tumorigenic effects. We examine the possible explanations for blood eosinophilia during NSCLC treatment with ICI. In particular, we discuss the value of eosinophils as a potential prognostic and predictive biomarker, highlighting the need for stronger clinical data. Finally, we conclude with perspectives on clinical and translational research topics on this subject. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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17 pages, 1270 KiB

Open AccessReview

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

by Glenn Van Hulst, Fabrice Bureau and Christophe J. Desmet

Int. J. Mol. Sci. 2021, 22(18), 10150; https://doi.org/10.3390/ijms221810150 - 21 Sep 2021

Cited by 21 | Viewed by 8454

Abstract

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells [...] Read more.

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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13 pages, 1302 KiB

Open AccessReview

Could the Epigenetics of Eosinophils in Asthma and Allergy Solve Parts of the Puzzle?

by Émile Bélanger and Catherine Laprise

Int. J. Mol. Sci. 2021, 22(16), 8921; https://doi.org/10.3390/ijms22168921 - 19 Aug 2021

Cited by 6 | Viewed by 2640

Abstract

Epigenetics is a field of study investigating changes in gene expression that do not alter the DNA sequence. These changes are often influenced by environmental or social factors and are reversible. Epigenetic mechanisms include DNA methylation, histone modification, and noncoding RNA. Understanding the [...] Read more.

Epigenetics is a field of study investigating changes in gene expression that do not alter the DNA sequence. These changes are often influenced by environmental or social factors and are reversible. Epigenetic mechanisms include DNA methylation, histone modification, and noncoding RNA. Understanding the role of these epigenetic mechanisms in human diseases provides useful information with regard to disease severity and development. Several studies have searched for the epigenetic mechanisms that regulate allergies and asthma; however, only few studies have used samples of eosinophil, a proinflammatory cell type known to be largely recruited during allergic or asthmatic inflammation. Such studies would enable us to better understand the factors that influence the massive recruitment of eosinophils during allergic and asthmatic symptoms. In this review, we sought to summarize different studies that aimed to discover differential patterns of histone modifications, DNA methylation, and noncoding RNAs in eosinophil samples of individuals with certain diseases, with a particular focus on those with asthma or allergic diseases. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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18 pages, 1264 KiB

Open AccessReview

Eosinophils and Bacteria, the Beginning of a Story

by Edna Ondari, Esther Calvino-Sanles, Nicholas J. First and Monica C. Gestal

Int. J. Mol. Sci. 2021, 22(15), 8004; https://doi.org/10.3390/ijms22158004 - 27 Jul 2021

Cited by 17 | Viewed by 4505

Abstract

Eosinophils are granulocytes primarily associated with T_H2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for [...] Read more.

Eosinophils are granulocytes primarily associated with T_H2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers T_H2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote T_H17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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19 pages, 9344 KiB

Open AccessReview

The Enigma of Eosinophil Degranulation

by Timothée Fettrelet, Lea Gigon, Alexander Karaulov, Shida Yousefi and Hans-Uwe Simon

Int. J. Mol. Sci. 2021, 22(13), 7091; https://doi.org/10.3390/ijms22137091 - 30 Jun 2021

Cited by 42 | Viewed by 8993

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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28 pages, 3349 KiB

Open AccessReview

Emerging Evidence for Pleiotropism of Eosinophils

by José M. Rodrigo-Muñoz, Marta Gil-Martínez, Beatriz Sastre and Victoria del Pozo

Int. J. Mol. Sci. 2021, 22(13), 7075; https://doi.org/10.3390/ijms22137075 - 30 Jun 2021

Cited by 24 | Viewed by 10215

Abstract

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific [...] Read more.

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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26 pages, 1337 KiB

Open AccessReview

Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases

by Eva Maria Sturm, Eva Knuplez and Gunther Marsche

Int. J. Mol. Sci. 2021, 22(9), 4377; https://doi.org/10.3390/ijms22094377 - 22 Apr 2021

Cited by 11 | Viewed by 3847

Abstract

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation [...] Read more.

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Despite the tremendous progress in the treatment of eosinophilic disorders with the implementation of biologics, there is an unmet need for novel therapies that specifically target the cytotoxic effector functions of eosinophils without completely depleting this multifunctional immune cell type. Recent studies have uncovered several endogenous molecules that decrease eosinophil migration and activation. These include short chain fatty acids (SCFAs) such as butyrate, which are produced in large quantities in the gastrointestinal tract by commensal bacteria and enter the systemic circulation. In addition, high-density lipoprotein-associated anti-inflammatory apolipoproteins have recently been shown to attenuate eosinophil migration and activation. Here, we focus on the anti-pathogenic properties of SCFAs and apolipoproteins on eosinophil effector function and provide insights into the potential use of SCFAs and apolipoproteins (and their mimetics) as effective agents to combat eosinophilic inflammation. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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29 pages, 1424 KiB

Open AccessReview

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

by Eva Knuplez, Eva Maria Sturm and Gunther Marsche

Int. J. Mol. Sci. 2021, 22(9), 4356; https://doi.org/10.3390/ijms22094356 - 21 Apr 2021

Cited by 7 | Viewed by 3700

Abstract

Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of [...] Read more.

Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

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