Sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating β2-integrin–dependent function in human eosinophils

Carroll, Daniela J.; O’Sullivan, Jeremy A.; Nix, David B.; Cao, Yun; Tiemeyer, Michael; Bochner, Bruce S.

doi:10.1016/j.jaci.2017.08.013

Cited by 42 publications

(70 citation statements)

References 62 publications

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“…It is not yet clear whether Siglec‐8 on the surface of mouse eosinophils leads to the activation of the same sets of kinases responsible for the pro‐apoptotic effect in human eosinophils or whether it engages the same endocytic machinery, both of which have recently been described . Given the weak pro‐apoptotic effects of Siglec‐F compared to the robust response to Siglec‐8, it is tempting to speculate that these pathways will turn out to be distinct.…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils

O’Sullivan

Wei

Carroll

et al. 2018

Journal of Leukocyte Biology

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Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a human cell surface protein expressed exclusively on eosinophils, mast cells, and basophils that, when engaged, induces eosinophil apoptosis and inhibits mast cell mediator release. This makes Siglec-8 a promising therapeutic target to treat diseases involving these cell types. However, preclinical studies of Siglec-8 targeting in vivo are lacking because this protein is only found in humans, apes, and some monkeys. Therefore, we have developed a mouse strain in which SIGLEC8 transcription is activated by Cre recombinase and have crossed this mouse with the eoCre mouse to achieve eosinophil-specific expression. We confirmed that Siglec-8 is expressed exclusively on the surface of mature eosinophils in multiple tissues at levels comparable to those on human blood eosinophils. Following ovalbumin sensitization and airway challenge, Siglec-8 knock-in mice generated a pattern of allergic lung inflammation indistinguishable from that of littermate controls, suggesting that Siglec-8 expression within the eosinophil compartment does not alter allergic eosinophilic inflammation. Using bone marrow from these mice, we demonstrated that, during maturation, Siglec-8 expression occurs well before the late eosinophil developmental marker C-C motif chemokine receptor 3, consistent with eoCre expression. Antibody ligation of the receptor induces Siglec-8 endocytosis and alters the phosphotyrosine profile of these cells, indicative of productive signaling. Finally, we demonstrated that mouse eosinophils expressing Siglec-8 undergo cell death when the receptor is engaged, further evidence that Siglec-8 is functional on these cells. These mice should prove useful to investigate Siglec-8 biology and targeting in vivo in a variety of eosinophilic disease models.

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Section: Discussionmentioning

confidence: 99%

Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils

O’Sullivan

Wei

Carroll

et al. 2018

Journal of Leukocyte Biology

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“…Whether other changes in the tissue microenvironment (e.g., during morphogenesis, aging, wound development, and repair) influence the biology of resident and recruited eosinophils is less clear. Cell surface lectin receptors, such as Siglec‐8, can engage specific glycan ligands on tissue and may selectively influence eosinophils . This bidirectional response and understanding of tissue microenvironments will be an important concept for future study in EADs.…”

Section: Resultsmentioning

confidence: 99%

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD)

Khoury

Akuthota

Ackerman

et al. 2018

Journal of Leukocyte Biology

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Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority.

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“…For example, IL‐5 priming in human eosinophils leaves them much more susceptible to Siglec‐8 mediated death, whereas in MCs Siglec‐8 ligation inhibits FcεRI‐dependent MC activation and calcium flux in an ITIM‐dependent manner . Other studies have highlighted the contribution of IL‐33 priming to Siglec‐8 mediated eosinophil apoptosis and demonstrated how Siglec‐8 ligation promoted eosinophil adhesion via β2 integrins that was necessary for apoptosis . In addition to Siglec‐8, Siglec‐10 expression has been detected on human eosinophils, however further studies are needed to determine its functional relevance.…”

Section: Cell Surface Receptorsmentioning

confidence: 99%

“…The primary role of ROS in inflammation is probably to eradicate invaders through their toxic effects . MCs can produce ROS upon IgE‐dependent activation and both MCs and eosinophils by activation of FcγR, Siglec‐8 or other receptors . ROS plays a role in the regulation of airway inflammation and remodeling via MC involvement in the VEGF production cascade .…”

Section: Mediators Released Upon Activationmentioning

confidence: 99%

“…63 In humans, Siglec-8 engagement has profound functional consequences on both MCs and eosinophils. 64 For example, IL-5 priming in human eosinophils leaves them much more susceptible to Siglec-8 mediated death, 65,66 whereas in MCs Siglec-8 ligation inhibits FcεRI-dependent MC activation and calcium flux in an ITIM-dependent manner. 67 Other studies have highlighted the contribution of IL-33 priming to Siglec-8 mediated eosinophil apoptosis and demonstrated how Siglec-8 ligation promoted eosinophil adhesion via β2 integrins that was necessary for apoptosis.…”

Section: Expression Ofmentioning

confidence: 99%

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Human eosinophils and mast cells: Birds of a feather flock together

Robida

Puzzovio

Pahima

et al. 2018

Immunological Reviews

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While the origin of the phrase "birds of a feather flock together" is unclear, it has been in use for centuries and is typically employed to describe the phenomenon that people with similar tastes or interests tend to seek each other out and congregate together. In this review, we have co-opted this phrase to compare innate immune cells of related origin, the eosinophil and mast cell, because they very often accumulate together in tissue sites under both homeostatic and inflammatory conditions. To highlight overlapping yet distinct features, their hematopoietic development, cell surface phenotype, mediator release profiles and roles in diseases have been compared and contrasted. What emerges is a sense that these two cell types often interact with each other and their tissue environment to provide synergistic contributions to a variety of normal and pathologic immune responses.

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Sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating β2-integrin–dependent function in human eosinophils

Abstract: These data demonstrate that Siglec-8 functions uniquely as an activating receptor on IL-5-primed eosinophils through a novel pathway involving regulation of β-integrin-dependent adhesion, NADPH oxidase, and a subset of protein kinases.

Cited by 42 publications

References 62 publications

Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils

Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD)

Human eosinophils and mast cells: Birds of a feather flock together

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