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
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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