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Editorial

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4 pages, 190 KiB

Open AccessEditorial

Eosinophils, beyond IL-5

by Stephane Esnault, Mats W Johansson and Sameer K Mathur

Cells 2021, 10(10), 2615; https://doi.org/10.3390/cells10102615 - 1 Oct 2021

Cited by 5 | Viewed by 2723

Abstract

New therapeutic monoclonal antibodies targeting the IL-5/IL-5 receptor pathway are extremely efficient in depleting blood eosinophils from subjects with asthma [...] Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

Research

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13 pages, 4288 KiB

Open AccessFeature PaperArticle

Autophagy Protects against Eosinophil Cytolysis and Release of DNA

by Stephane Esnault, Paul S. Fichtinger, Karina T. Barretto, Frances J. Fogerty, Ksenija Bernau, Deane F. Mosher, Sameer K. Mathur, Nathan Sandbo and Nizar N. Jarjour

Cells 2022, 11(11), 1821; https://doi.org/10.3390/cells11111821 - 2 Jun 2022

Cited by 8 | Viewed by 2172

Abstract

The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Eosinophils deposit their damaging products in airway tissue, likely by degranulation and cytolysis. We previously showed that priming blood eosinophils with IL3 strongly increased their cytolysis on [...] Read more.

The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Eosinophils deposit their damaging products in airway tissue, likely by degranulation and cytolysis. We previously showed that priming blood eosinophils with IL3 strongly increased their cytolysis on aggregated IgG. Conversely, IL5 priming did not result in significant eosinophil cytolysis in the same condition. Therefore, to identify critical events protecting eosinophils from cell cytolysis, we examined the differential intracellular events between IL5- and IL3-primed eosinophils interacting with IgG. We showed that both IL3 and IL5 priming increased the eosinophil adhesion to IgG, phosphorylation of p38, and production of reactive oxygen species (ROS), and decreased the phosphorylation of cofilin. However, autophagic flux as measured by the quantification of SQSTM1-p62 and lipidated-MAP1L3CB over time on IgG, with or without bafilomycin-A1, was higher in IL5-primed compared to IL3-primed eosinophils. In addition, treatment with bafilomycin-A1, an inhibitor of granule acidification and autophagolysosome formation, enhanced eosinophil cytolysis and DNA trap formation in IL5-primed eosinophils. Therefore, this study suggests that increased autophagy in eosinophils protects from cytolysis and the release of DNA, and thus limits the discharge of damaging intracellular eosinophilic contents. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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12 pages, 1721 KiB

Open AccessFeature PaperArticle

The Systemic Immune Response in COVID-19 Is Associated with a Shift to Formyl-Peptide Unresponsive Eosinophils

by Leo Koenderman, Maarten J. Siemers, Corneli van Aalst, Suzanne H. Bongers, Roy Spijkerman, Bas J. J. Bindels, Giulio Giustarini, Harriët M. R. van Goor, Karin A. H. Kaasjager and Nienke Vrisekoop

Cells 2021, 10(5), 1109; https://doi.org/10.3390/cells10051109 - 5 May 2021

Cited by 10 | Viewed by 3074

Abstract

A malfunction of the innate immune response in COVID-19 is associated with eosinopenia, particularly in more severe cases. This study tested the hypothesis that this eosinopenia is COVID-19 specific and is associated with systemic activation of eosinophils. Blood of 15 healthy controls and [...] Read more.

A malfunction of the innate immune response in COVID-19 is associated with eosinopenia, particularly in more severe cases. This study tested the hypothesis that this eosinopenia is COVID-19 specific and is associated with systemic activation of eosinophils. Blood of 15 healthy controls and 75 adult patients with suspected COVID-19 at the ER were included before PCR testing and analyzed by point-of-care automated flow cytometry (CD10, CD11b, CD16, and CD62L) in the absence or presence of a formyl peptide (fNLF). Forty-five SARS-CoV-2 PCR positive patients were grouped based on disease severity. PCR negative patients with proven bacterial (n = 20) or other viral (n = 10) infections were used as disease controls. Eosinophils were identified with the use of the FlowSOM algorithm. Low blood eosinophil numbers (<100 cells/μL; p < 0.005) were found both in patients with COVID-19 and with other infectious diseases, albeit less pronounced. Two discrete eosinophil populations were identified in healthy controls both before and after activation with fNLF based on the expression of CD11b. Before activation, the CD11b^bright population consisted of 5.4% (CI_95% = 3.8, 13.4) of total eosinophils. After activation, this population of CD11b^bright cells comprised nearly half the population (42.21%, CI_95% = 35.9, 54.1). Eosinophils in COVID-19 had a similar percentage of CD11b^bright cells before activation (7.6%, CI_95% = 4.5, 13.6), but were clearly refractory to activation with fNLF as a much lower percentage of cells end up in the CD11b^bright fraction after activation (23.7%, CI_95% = 18.5, 27.6; p < 0.001). Low eosinophil numbers in COVID-19 are associated with refractoriness in responsiveness to fNLF. This might be caused by migration of fully functional cells to the tissue. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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12 pages, 1731 KiB

Open AccessArticle

Beyond Il-5: Metabolic Reprogramming and Stromal Support Are Prerequisite for Generation and Survival of Long-Lived Eosinophil

by Mackenzie E. Coden, Matthew T. Walker, Brian M. Jeong, Andrew R. Connelly, Reina Nagasaka and Sergejs Berdnikovs

Cells 2021, 10(4), 815; https://doi.org/10.3390/cells10040815 - 6 Apr 2021

Cited by 6 | Viewed by 3299

Abstract

Eosinophils play surprisingly diverse roles in health and disease. Accordingly, we have now begun to appreciate the scope of the functional and phenotypic heterogeneity and plasticity of these cells. Along with tissue-recruited subsets during inflammation, there are tissue resident eosinophil phenotypes with potentially [...] Read more.

Eosinophils play surprisingly diverse roles in health and disease. Accordingly, we have now begun to appreciate the scope of the functional and phenotypic heterogeneity and plasticity of these cells. Along with tissue-recruited subsets during inflammation, there are tissue resident eosinophil phenotypes with potentially longer life spans and less dependency on IL-5 for survival. Current models to study murine eosinophils ex vivo rely on IL-5-sustained expansion of eosinophils from bone marrow hematopoietic progenitors. Although it does generate eosinophils (bmEos) in high purity, such systems are short-lived (14 days on average) and depend on IL-5. In this report, we present a novel method of differentiating large numbers of pure bone marrow-derived eosinophils with a long-lived phenotype (llEos) (40 days on average) that require IL-5 for initial differentiation, but not for subsequent survival. We identified two key factors in the development of llEos: metabolic adaptation and reprogramming induced by suppressed nutrient intake during active differentiation (from Day 7 of culture), and interaction with IL-5-primed stromal cells for the remainder of the protocol. This regimen results in a higher yield and viability of mature eosinophils. Phenotypically, llEos develop as Siglec-F(+)Ly6G(+) cells transitioning to Siglec-F(+) only, and exhibit typical eosinophil features with red eosin granular staining, as well as the ability to chemotax to eotaxin Ccl11 and process fibrinogen. This culture system requires less reagent input and allows us to study eosinophils long-term, which is a significant improvement over IL-5-driven differentiation protocols. Moreover, it provides important insights into factors governing eosinophil plasticity and the ability to assume long-lived IL-5-independent phenotypes. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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17 pages, 3401 KiB

Open AccessArticle

Interleukin-1α Is a Critical Mediator of the Response of Human Bronchial Fibroblasts to Eosinophilic Inflammation

by Ksenija Bernau, Jonathan P. Leet, Heather Floerke, Ellen M. Bruhn, Andrea L. Noll, Ivy S. McDermott, Stephane Esnault, Nizar N. Jarjour and Nathan Sandbo

Cells 2021, 10(3), 528; https://doi.org/10.3390/cells10030528 - 2 Mar 2021

Cited by 8 | Viewed by 2293

Abstract

Eosinophils contribute to allergic inflammation in asthma in part via elaboration of a complex milieu of soluble mediators. Human bronchial fibroblasts (HBF) respond to stimulation by these mediators by acquiring a pro-inflammatory profile including induction of interleukin 6 (IL6) and IL8. This study [...] Read more.

Eosinophils contribute to allergic inflammation in asthma in part via elaboration of a complex milieu of soluble mediators. Human bronchial fibroblasts (HBF) respond to stimulation by these mediators by acquiring a pro-inflammatory profile including induction of interleukin 6 (IL6) and IL8. This study sought to determine key component(s) of eosinophil soluble factors that mediate IL6 and IL8 induction in HBF. HBF treated with eosinophil-derived soluble mediators were analyzed for gene expression, intracellular signaling, and IL6 and IL8 secretion following inhibition of inflammatory signaling. Segmental allergen bronchoprovocation (SBP-Ag) was performed in mild asthmatics and bronchoalveolar lavage fluid was analyzed for eosinophils and cytokines. We found that signaling via the IL1α/IL1 receptor is an essential component of the response of HBF to eosinophil-derived soluble factors. IL1α-dependent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling is required to induce IL6 secretion. However, NFκB signaling is dispensable for the induction of IL8, whereas Src is required. IL1α is associated with eosinophilic inflammation in human airways after SBP-Ag. Conclusions: IL1α appears to be a critical component of the soluble eosinophil-derived milieu that drives pro-inflammatory bronchial fibroblast responses and associates with eosinophilic inflammation following SBP-Ag. Disruption of IL1α-signaling could modify the downstream effects of eosinophilic inflammation on airway remodeling. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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24 pages, 5404 KiB

Open AccessArticle

Eosinophil Responses at the Airway Epithelial Barrier during the Early Phase of Influenza a Virus Infection in C57BL/6 Mice

by Meenakshi Tiwary, Robert J. Rooney, Swantje Liedmann, Kim S. LeMessurier and Amali E. Samarasinghe

Cells 2021, 10(3), 509; https://doi.org/10.3390/cells10030509 - 27 Feb 2021

Cited by 18 | Viewed by 4467

Abstract

Eosinophils, previously considered terminally differentiated effector cells, have multifaceted functions in tissues. We previously found that allergic mice with eosinophil-rich inflammation were protected from severe influenza and discovered specialized antiviral effector functions for eosinophils including promoting cellular immunity during influenza. In this study, [...] Read more.

Eosinophils, previously considered terminally differentiated effector cells, have multifaceted functions in tissues. We previously found that allergic mice with eosinophil-rich inflammation were protected from severe influenza and discovered specialized antiviral effector functions for eosinophils including promoting cellular immunity during influenza. In this study, we hypothesized that eosinophil responses during the early phase of influenza contribute to host protection. Using in vitro and in vivo models, we found that eosinophils were rapidly and dynamically regulated upon influenza A virus (IAV) exposure to gain migratory capabilities to traffic to lymphoid organs after pulmonary infection. Eosinophils were capable of neutralizing virus upon contact and combinations of eosinophil granule proteins reduced virus infectivity through hemagglutinin inactivation. Bi-directional crosstalk between IAV-exposed epithelial cells and eosinophils occurred after IAV infection and cross-regulation promoted barrier responses to improve antiviral defenses in airway epithelial cells. Direct interactions between eosinophils and airway epithelial cells after IAV infection prevented virus-induced cytopathology in airway epithelial cells in vitro, and eosinophil recipient IAV-infected mice also maintained normal airway epithelial cell morphology. Our data suggest that eosinophils are important in the early phase of IAV infection providing immediate protection to the epithelial barrier until adaptive immune responses are deployed during influenza. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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15 pages, 2648 KiB

Open AccessArticle

The Release Kinetics of Eosinophil Peroxidase and Mitochondrial DNA Is Different in Association with Eosinophil Extracellular Trap Formation

by Nina Germic, Timothée Fettrelet, Darko Stojkov, Aref Hosseini, Michael P. Horn, Alexander Karaulov, Dagmar Simon, Shida Yousefi and Hans-Uwe Simon

Cells 2021, 10(2), 306; https://doi.org/10.3390/cells10020306 - 3 Feb 2021

Cited by 18 | Viewed by 4136

Abstract

Eosinophils are a subset of granulocytes characterized by a high abundance of specific granules in their cytoplasm. To act as effector cells, eosinophils degranulate and form eosinophil extracellular traps (EETs), which contain double-stranded DNA (dsDNA) co-localized with granule proteins. The exact molecular mechanism [...] Read more.

Eosinophils are a subset of granulocytes characterized by a high abundance of specific granules in their cytoplasm. To act as effector cells, eosinophils degranulate and form eosinophil extracellular traps (EETs), which contain double-stranded DNA (dsDNA) co-localized with granule proteins. The exact molecular mechanism of EET formation remains unknown. Although the term “EET release” has been used in scientific reports, it is unclear whether EETs are pre-formed in eosinophils and subsequently released. Moreover, although eosinophil degranulation has been extensively studied, a precise time-course of granule protein release has not been reported until now. In this study, we investigated the time-dependent release of eosinophil peroxidase (EPX) and mitochondrial DNA (mtDNA) following activation of both human and mouse eosinophils. Unexpectedly, maximal degranulation was already observed within 1 min with no further change upon complement factor 5 (C5a) stimulation of interleukin-5 (IL-5) or granulocyte/macrophage colony-stimulating factor (GM-CSF)-primed eosinophils. In contrast, bulk mtDNA release in the same eosinophil populations occurred much slower and reached maximal levels between 30 and 60 min. Although no single-cell analyses have been performed, these data suggest that the molecular pathways leading to degranulation and mtDNA release are at least partially different. Moreover, based on these data, it is likely that the association between the mtDNA scaffold and granule proteins in the process of EET formation occurs in the extracellular space. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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12 pages, 1837 KiB

Open AccessArticle

Pin1 Regulates IL-5 Induced Eosinophil Polarization and Migration

by Zhong-Jian Shen, Jie Hu, Melissa A. O’Neal and James S. Malter

Cells 2021, 10(2), 211; https://doi.org/10.3390/cells10020211 - 21 Jan 2021

Cited by 6 | Viewed by 2750

Abstract

Eosinophils become polarized in response to cytokines such IL-5 or eotaxin prior to directional migration. Polarization is preceded by F-actin assembly, but the mechanisms that regulate these events and how the shape change influences cell migration from the peripheral blood into the lung [...] Read more.

Eosinophils become polarized in response to cytokines such IL-5 or eotaxin prior to directional migration. Polarization is preceded by F-actin assembly, but the mechanisms that regulate these events and how the shape change influences cell migration from the peripheral blood into the lung remain unclear. In this study, we show that the prolyl isomerase, Pin1, is required for IL-5-induced Eos polarization and migration. Co-immunoprecipitation and immunofluorescence analysis revealed that Pin1 directly interacts with members of Rho GTPase family. Mouse eosinophils lacking Pin1 or human cells treated with Pin1 inhibitors showed significantly reduced IL-5-induced GTPase activity and cofilin phosphorylation, resulting in reduced F-actin polymerization, cell polarization, and directional migration to chemokines. Our result suggests that Pin1 regulates cytoskeletal re-organization, eosinophil morphology, and cell migration through the modulation of Rho GTPase activity. Targeting Pin1 along with GTPases could provide a new approach to reduce pulmonary Eos accumulation during asthmatic exacerbations. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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12 pages, 1842 KiB

Open AccessArticle

The Cycling of Intracellular Calcium Released in Response to Fluid Shear Stress Is Critical for Migration-Associated Actin Reorganization in Eosinophils

by Kiho Son, Amer Hussain, Roma Sehmi and Luke Janssen

Cells 2021, 10(1), 157; https://doi.org/10.3390/cells10010157 - 15 Jan 2021

Cited by 6 | Viewed by 2745

Abstract

The magnitude of eosinophil mobilization into respiratory tissues drives the severity of inflammation in several airway diseases. In classical models of leukocyte extravasation, surface integrins undergo conformational switches to high-affinity states via chemokine binding activation. Recently, we learned that eosinophil integrins possess mechanosensitive [...] Read more.

The magnitude of eosinophil mobilization into respiratory tissues drives the severity of inflammation in several airway diseases. In classical models of leukocyte extravasation, surface integrins undergo conformational switches to high-affinity states via chemokine binding activation. Recently, we learned that eosinophil integrins possess mechanosensitive properties that detect fluid shear stress, which alone was sufficient to induce activation. This mechanical stimulus triggered intracellular calcium release and hallmark migration-associated cytoskeletal reorganization including flattening for increased cell–substratum contact area and pseudopodia formation. The present study utilized confocal fluorescence microscopy to investigate the effects of pharmacological inhibitors to calcium signaling and actin polymerization pathways on shear stress-induced migration in vitro. Morphological changes (cell elongation, membrane protrusions) succeeded the calcium flux in untreated eosinophils within 2 min, suggesting that calcium signaling was upstream of actin cytoskeleton rearrangement. The inhibition of ryanodine receptors and endomembrane Ca²⁺-ATPases corroborated this idea, indicated by a significant increase in time between the calcium spike and actin polymerization. The impact of the temporal link is evident as the capacity of treated eosinophils to move across fibronectin-coated surfaces was significantly hampered relative to untreated eosinophils. Furthermore, we determined that the nature of cellular motility in response to fluid shear stress was nondirectional. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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Review

Jump to: Editorial, Research

18 pages, 1338 KiB

Open AccessReview

Basophils Orchestrating Eosinophils’ Chemotaxis and Function in Allergic Inflammation

by Joseena Iype and Michaela Fux

Cells 2021, 10(4), 895; https://doi.org/10.3390/cells10040895 - 14 Apr 2021

Cited by 33 | Viewed by 6539

Abstract

Eosinophils are well known to contribute significantly to Th2 immunity, such as allergic inflammations. Although basophils have often not been considered in the pathogenicity of allergic dermatitis and asthma, their role in Th2 immunity has become apparent in recent years. Eosinophils and basophils [...] Read more.

Eosinophils are well known to contribute significantly to Th2 immunity, such as allergic inflammations. Although basophils have often not been considered in the pathogenicity of allergic dermatitis and asthma, their role in Th2 immunity has become apparent in recent years. Eosinophils and basophils are present at sites of allergic inflammations. It is therefore reasonable to speculate that these two types of granulocytes interact in vivo. In various experimental allergy models, basophils and eosinophils appear to be closely linked by directly or indirectly influencing each other since they are responsive to similar cytokines and chemokines. Indeed, basophils are shown to be the gatekeepers that are capable of regulating eosinophil entry into inflammatory tissue sites through activation-induced interactions with endothelium. However, the direct evidence that eosinophils and basophils interact is still rarely described. Nevertheless, new findings on the regulation and function of eosinophils and basophils biology reported in the last 25 years have shed some light on their potential interaction. This review will focus on the current knowledge that basophils may regulate the biology of eosinophil in atopic dermatitis and allergic asthma. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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23 pages, 742 KiB

Open AccessFeature PaperReview

Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment

by Ruth P. Cusack, Christiane E. Whetstone, Yanqing Xie, Maral Ranjbar and Gail M. Gauvreau

Cells 2021, 10(4), 817; https://doi.org/10.3390/cells10040817 - 6 Apr 2021

Cited by 16 | Viewed by 4789

Abstract

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is [...] Read more.

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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21 pages, 1037 KiB

Open AccessReview

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

by Joanne C. Masterson, Calies Menard-Katcher, Leigha D. Larsen, Glenn T. Furuta and Lisa A. Spencer

Cells 2021, 10(2), 426; https://doi.org/10.3390/cells10020426 - 17 Feb 2021

Cited by 19 | Viewed by 4717

Abstract

Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some [...] Read more.

Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some endotypes of EGIDs. However, destructive effector functions of eosinophils are only one side of the coin; eosinophils also play important roles in immune and tissue homeostasis. A growing body of data suggest tissue eosinophils represent a plastic and heterogeneous population of functional sub-phenotypes, shaped by environmental (systemic and local) pressures, which may differentially impact disease outcomes. This may be particularly relevant to the GI tract, wherein the highest density of eosinophils reside in the steady state, resident immune cells are exposed to an especially broad range of external and internal environmental pressures, and greater eosinophil longevity may uniquely enrich for co-expression of eosinophil sub-phenotypes. Here we review the growing evidence for functional sub-phenotypes of intestinal tissue eosinophils, with emphasis on the multifactorial pressures that shape and diversify eosinophil identity and potential targets to inform next-generation eosinophil-targeting strategies designed to restrain inflammatory eosinophil functions while sustaining homeostatic roles. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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17 pages, 2780 KiB

Open AccessReview

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

by Brittany M. Salter, Xiaotian Ju and Roma Sehmi

Cells 2021, 10(2), 412; https://doi.org/10.3390/cells10020412 - 16 Feb 2021

Cited by 12 | Viewed by 4424

Abstract

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia [...] Read more.

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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14 pages, 1273 KiB

Open AccessReview

Discovery, Function, and Therapeutic Targeting of Siglec-8

by Bradford A. Youngblood, John Leung, Rustom Falahati, Jason Williams, Julia Schanin, Emily C. Brock, Bhupinder Singh, Alan T. Chang, Jeremy A. O’Sullivan, Robert P. Schleimer, Nenad Tomasevic, Christopher R. Bebbington and Bruce S. Bochner

Cells 2021, 10(1), 19; https://doi.org/10.3390/cells10010019 - 24 Dec 2020

Cited by 60 | Viewed by 9257

Abstract

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate [...] Read more.

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases. Full article

(This article belongs to the Special Issue Eosinophils beyond IL-5)

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