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Siglec-F Promotes IL-33–Induced Cytokine Release from Bone Marrow–Derived Eosinophils Independently of the ITIM and ITIM-like Motif Phosphorylation

Stefanie Westermann, Axel Dietschmann, Daniela Doehler, Kirstin Castiglione, Bruce S. Bochner, David Voehringer and Daniel Radtke
J Immunol February 1, 2022, 208 (3) 732-744; DOI: https://doi.org/10.4049/jimmunol.2100184
Stefanie Westermann
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Axel Dietschmann
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Daniela Doehler
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Kirstin Castiglione
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Bruce S. Bochner
†Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
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David Voehringer
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Daniel Radtke
*Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; and
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Key Points

  • Siglec-F does not dampen A. fumigatus–elicited lung eosinophilia.

  • Siglec-F cross-linking enhances mediator release from IL-33–stimulated eosinophils.

  • This effect depends on the cytoplasmic tail, but not the ITIM/ITIM-like motifs.

Visual Abstract

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Abstract

Eosinophils are potent innate effector cells associated mainly with type 2 immune responses elicited by helminths and allergens. Their activity needs to be tightly controlled to prevent severe inflammation and tissue damage. Eosinophil degranulation and secretion of inflammatory effector molecules, including cytokines, chemokines, and lipid mediators, can be regulated by activating and inhibitory receptors on the cell surface. In this study, we investigated the modulation of proliferation, apoptosis, gene expression, and cytokine/chemokine secretion from IL-33–activated Mus musculus eosinophils on cross-linking of the transmembrane receptor Sialic acid–binding Ig-like lectin F (Siglec-F). Siglec-F contains an ITIM plus an ITIM-like motif in its intracellular tail and is mainly regarded as an inhibitory and apoptosis-inducing receptor. In vitro costimulation of bone marrow–derived eosinophils with anti–Siglec-F and IL-33 compared with treatment with either alone led to enhanced STAT6 phosphorylation, stronger induction of hypoxia/glycolysis-related proinflammatory genes, and elevated secretion of type 2 cytokines (IL-4, IL-13) and chemokines (CCL3, CCL4) with only minor effects on proliferation and apoptosis. Using a competitive mixed bone marrow chimera approach with wild-type and Siglec-F–deficient eosinophils, we observed no evidence for Siglec-F–regulated inhibition of Aspergillus fumigatus–elicited lung eosinophilia. Truncation of the Siglec-F cytoplasmic tail, but not mutation of the ITIM and ITIM-like motifs, ablated the effect of enhanced cytokine/chemokine secretion. This provides evidence for an ITIM phosphorylation-independent signaling pathway from the cytoplasmic tail of the Siglec-F receptor that enhances effector molecule release from activated eosinophils.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft (Grants VO944/9-1 and CRC1181_A02 to D.V.) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Grant U19 AI136443 to B.S.B.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    BMDE
    bone marrow–derived eosinophil
    ECM
    eosinophil culture medium
    MBMC
    mixed bone marrow chimera
    MIF
    migration inhibitory factor
    SHP
    Src homology region 2 domain-containing phosphatase 1
    Siglec-F
    sialic acid–binding Ig-like lectin F

  • Received February 24, 2021.
  • Accepted November 19, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (3)
The Journal of Immunology
Vol. 208, Issue 3
1 Feb 2022
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Siglec-F Promotes IL-33–Induced Cytokine Release from Bone Marrow–Derived Eosinophils Independently of the ITIM and ITIM-like Motif Phosphorylation
Stefanie Westermann, Axel Dietschmann, Daniela Doehler, Kirstin Castiglione, Bruce S. Bochner, David Voehringer, Daniel Radtke
The Journal of Immunology February 1, 2022, 208 (3) 732-744; DOI: 10.4049/jimmunol.2100184

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Siglec-F Promotes IL-33–Induced Cytokine Release from Bone Marrow–Derived Eosinophils Independently of the ITIM and ITIM-like Motif Phosphorylation
Stefanie Westermann, Axel Dietschmann, Daniela Doehler, Kirstin Castiglione, Bruce S. Bochner, David Voehringer, Daniel Radtke
The Journal of Immunology February 1, 2022, 208 (3) 732-744; DOI: 10.4049/jimmunol.2100184
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