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Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating ?2-integrin-dependent function in human eosinophils.

ABSTRACT: BACKGROUND:Siglec-8 is a CD33 subfamily cell-surface receptor selectively expressed on human eosinophils. After cytokine priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 might instead function as an activating receptor. OBJECTIVE:We sought to determine the role of IL-5 priming and identify the signaling molecules involved in Siglec-8 function for human eosinophils. METHODS:We used an mAb and/or a multimeric synthetic sulfated sialoglycan ligand recognizing Siglec-8 in combination with integrin blocking antibodies, pharmacologic inhibitors, phosphoproteomics, and Western blot analysis to define the necessity of various proteins involved in Siglec-8 function for human eosinophils. RESULTS:Cytokine priming was required to elicit the unanticipated finding that Siglec-8 engagement promotes rapid ?2-integrin-dependent eosinophil adhesion. Also novel was the finding that this adhesion was necessary for subsequent ROS production and apoptosis. Siglec-8-mediated ROS was generated through reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation because pretreatment of eosinophils with catalase (an extracellular superoxide scavenger) or NSC 23766 (a Rac GTPase inhibitor) completely inhibited Siglec-8-mediated eosinophil apoptosis. Finally, engagement of Siglec-8 on IL-5-primed eosinophils resulted in increased phosphorylation of Akt, p38, and c-Jun N-terminal kinase 1 that was also ?2-integrin dependent; pharmacologic inhibition of these kinases completely prevented Siglec-8-mediated eosinophil apoptosis. CONCLUSIONS:These data demonstrate that Siglec-8 functions uniquely as an activating receptor on IL-5-primed eosinophils through a novel pathway involving regulation of ?2-integrin-dependent adhesion, NADPH oxidase, and a subset of protein kinases.

SUBMITTER: Carroll DJ

PROVIDER: S-EPMC5839929 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating β<sub>2</sub>-integrin-dependent function in human eosinophils.

Carroll Daniela J DJ O'Sullivan Jeremy A JA Nix David B DB Cao Yun Y Tiemeyer Michael M Bochner Bruce S BS

The Journal of allergy and clinical immunology 20170906 6

<h4>Background</h4>Siglec-8 is a CD33 subfamily cell-surface receptor selectively expressed on human eosinophils. After cytokine priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 might instead function as an activating receptor.<h4>Objective</h4>We soug ...[more]

PMID: 28888781

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Project description:ImportanceSialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a novel immune checkpoint molecule that is highly homologous to programmed cell death ligand 1 (PD-L1), but information remains limited about its role in esophageal squamous cell carcinoma (ESCC).ObjectiveTo explore the expression pattern and association of Siglec-15 with outcomes among patients with ESCC who received neoadjuvant chemoradiotherapy (CRT).Design, setting, and participantsThis retrospective cohort study was conducted at an academic institution in China. Participants included patients with ESCC who underwent neoadjuvant CRT and esophagectomy between June 2002 and December 2018. Multiplexed immunofluorescence staining was used to evaluate the expression of Siglec-15 and PD-L1 in tumor cells (TCs) or tumor-associated macrophages based on pre-CRT biopsies. Different immune phenotypes have been proposed and further validated in an independent cohort. Data analysis was conducted from January to May 2021.ExposuresSiglec-15 or PD-L1 positivity vs negativity.Main outcomes and measuresPathologic complete response (pCR), overall survival (OS), and recurrence-free survival (RFS).ResultsOf 130 participants (median [range] age, 56 [42-73] years; 108 [83.1%] male participants) in the primary cohort, 58 patients (44.6%) achieved a pCR after neoadjuvant CRT. Siglec-15 and PD-L1 were detected in both TCs and macrophages. The percentage of Siglec-15-positive macrophages was notably higher than that of Siglec-15-positive TCs (median [IQR]: 34.4% [12.7%-64.3%] vs 4.8% [0.7%-25.6%]; P < .001). TC-Siglec-15 expression was significantly and positively associated with macrophage-Siglec-15 expression (r = 0.78; P < .001). Siglec-15 positivity was significantly associated with a higher rate of pCR (37 of 70 [52.9%] vs 21 of 60 [35.0%]; P = .04), more favorable OS (hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01), and RFS (HR, 0.48; 95% CI, 0.26-0.88; P = .02). However, PD-L1 positivity in TCs was negatively associated with survival. Stratification analysis further revealed that patients with combined Siglec-15 positivity and PD-L1 negativity had better survival than those with other phenotypes. Major findings were reproducible in a validation cohort with 55 patients.Conclusions and relevanceIn this cohort study of patients with ESCC receiving neoadjuvant CRT, Siglec-15 positivity was associated with a better pathological response and more favorable survival. Siglec-15 could serve as a novel biomarker to identify potential candidates that may benefit from immunotherapy combined with CRT.

Dataset Information

Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating ?2-integrin-dependent function in human eosinophils.

Publications

Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating β<sub>2</sub>-integrin-dependent function in human eosinophils.

Similar Datasets

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