Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils

Abstract

CD33-related Siglecs (CD33rSiglecs) are a family of sialic acid–recognizing lectins on immune cells whose biologic functions are unknown. We studied in vivo functions of Siglec-F, the CD33rSiglec expressed on mouse eosinophils, which are prominent in allergic processes. Induction of allergic lung inflammation in mice caused up-regulation of Siglec-F on blood and bone marrow eosinophils, accompanied by newly induced expression on some CD4+ cells, as well as quantitative up-regulation of endogenous Siglec-F ligands in the lung tissue and airways. Taken together with the tyrosine-based inhibitory motif in the cytosolic tail of Siglec-F, the data suggested a negative feedback loop, controlling allergic responses of eosinophils and helper T cells, via Siglec-F and Siglec-F ligands. To pursue this hypothesis, we created Siglec-F–null mice. Allergen-challenged null mice showed increased lung eosinophil infiltration, enhanced bone marrow and blood eosinophilia, delayed resolution of lung eosinophilia, and reduced peribronchial-cell apoptosis. Anti–Siglec-F antibody cross-linking also enhanced eosinophil apoptosis in vitro. These data support the proposed negative feedback role for Siglec-F, represent the first in vivo demonstration of biologic functions for any CD33rSiglec, and predict a role for human Siglec-8 (the isofunctional paralog of mouse Siglec-F) in regulating the pathogenesis of human eosinophil-mediated disorders.

CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

“…Siglec-F is a sialic acid-recognizing lectin present on the surface of mouse eosinophils and is upregulated during allergic lung inflammation (40). Other cells, including pulmonary macrophages, may also express Siglec-F but are successfully excluded by costaining with CD11c, with the CD11c-negative population of Siglec-F-positive lung cells identifying eosinophils (35).…”

Analysis of Eosinophil Turnover In Vivo Reveals Their Active Recruitment to and Prolonged Survival in the Peritoneal Cavity

“…Siglec-F, a recently identified inhibitory receptor on mouse eosinophils and its human functional homologue Siglec-8 have been shown to induce apoptosis when crosslinked in vitro by mAbs (12,13). It remains to be determined whether Siglec-F can act as inhibitory receptor and regulate degranulation of eosinophils.…”

Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

“…8,9 Furthermore, mice deficient in mouse Siglec-F have exaggerated allergic lung eosinophilic responses. 10 These findings underscore the importance of Siglec-F/8 in eosinophil apoptosis and human eosinophil-mediated disorders like asthma.…”

“…3 Of interest, murine Siglec-8 variations and asthma P-S Gao et al studies targeting Siglec-F, the closest functional paralog to Siglec-8, also demonstrated a significant role in regulating the pathogenesis of eosinophil-mediated disorders. [8][9][10] As eosinophils and their many biologically active mediators are associated with allergic diseases and other chronic inflammatory disorders, this suggests that Siglec-8 could be a candidate gene for human eosinophilic disorders like asthma and EE.…”