Fanny Legrand1, Nadine Landolina2, Ilan Zaffran2, Robert O Emeh1, Elizabeth Chen1,3, Amy D Klion1, Francesca Levi-Schaffer2. 1. Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. 2. Pharmacology and Experimental Therapeutics Unit, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. 3. University of Maryland, College Park, Maryland.
Abstract
BACKGROUND: Siglec-7 is an inhibitory receptor (IR) expressed on human blood eosinophils. Whereas activation of other IRs, including Siglec-8 and CD300a, has been shown to downregulate eosinophil function, little is known about the role of Siglec-7 on human eosinophils. OBJECTIVE: To examine Siglec-7 expression and function in eosinophils from normal (ND) and eosinophilic (EO) donors. METHODS: Eosinophil expression of Siglec-7 was quantified by flow cytometry and quantitative PCR. Soluble Siglec-7 (sSiglec-7) levels were measured by ELISA in serum. The effect of Siglec-7 on eosinophil viability and degranulation was assessed in vitro by AnnexinV-FITC/7-AAD staining and by measuring GM-CSF-induced mediator release in culture supernatants. Signal transduction was studied by Western blot. RESULTS: Siglec-7 was expressed ex vivo on blood eosinophils from all eosinophilic and normal individuals studied. Siglec-7 surface, but not SIGLEC-7mRNA expression, was correlated with absolute eosinophil count (AEC). Siglec-7 was upregulated on purified eosinophils after in vitro stimulation with GM-CSF or IL-5. Serum sSiglec-7 was detectable in 133/144 subjects tested and correlated with AEC. Siglec-7 cross-linking inhibited GM-CSF-induced release of eosinophil peroxidase, TNF-α, and IL-8 (n = 7-8) but did not promote eosinophil apoptosis (n = 5). Finally, Siglec-7 cross-linking on GM-CSF-activated eosinophils induced phosphorylation of SHP-1 and de-phosphorylation of ERK1/2 and p38. CONCLUSIONS: Siglec-7 is constitutively expressed on human eosinophils and downmodulates eosinophil activation. Targeting of Siglec-7 on eosinophils might enhance treatment efficacy in eosinophil-driven disorders. Conversely, therapeutic interventions that inhibit Siglec-7 could have unanticipated consequences and promote eosinophilic inflammation.
BACKGROUND:Siglec-7 is an inhibitory receptor (IR) expressed on human blood eosinophils. Whereas activation of other IRs, including Siglec-8 and CD300a, has been shown to downregulate eosinophil function, little is known about the role of Siglec-7 on human eosinophils. OBJECTIVE: To examine Siglec-7 expression and function in eosinophils from normal (ND) and eosinophilic (EO) donors. METHODS: Eosinophil expression of Siglec-7 was quantified by flow cytometry and quantitative PCR. Soluble Siglec-7 (sSiglec-7) levels were measured by ELISA in serum. The effect of Siglec-7 on eosinophil viability and degranulation was assessed in vitro by AnnexinV-FITC/7-AAD staining and by measuring GM-CSF-induced mediator release in culture supernatants. Signal transduction was studied by Western blot. RESULTS:Siglec-7 was expressed ex vivo on blood eosinophils from all eosinophilic and normal individuals studied. Siglec-7 surface, but not SIGLEC-7mRNA expression, was correlated with absolute eosinophil count (AEC). Siglec-7 was upregulated on purified eosinophils after in vitro stimulation with GM-CSF or IL-5. Serum sSiglec-7 was detectable in 133/144 subjects tested and correlated with AEC. Siglec-7 cross-linking inhibited GM-CSF-induced release of eosinophil peroxidase, TNF-α, and IL-8 (n = 7-8) but did not promote eosinophil apoptosis (n = 5). Finally, Siglec-7 cross-linking on GM-CSF-activated eosinophils induced phosphorylation of SHP-1 and de-phosphorylation of ERK1/2 and p38. CONCLUSIONS:Siglec-7 is constitutively expressed on human eosinophils and downmodulates eosinophil activation. Targeting of Siglec-7 on eosinophils might enhance treatment efficacy in eosinophil-driven disorders. Conversely, therapeutic interventions that inhibit Siglec-7 could have unanticipated consequences and promote eosinophilic inflammation.
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