Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils.
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.
Zhang
Mai
M
Glycobiology Research and Training Center, Departments of Medicine and Cellular & Molecular Medicine, and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093-0687, USA.
Angata
Takashi
T
Cho
Jae Youn
JY
Miller
Marina
M
Broide
David H
DH
Varki
Ajit
A
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001985:Bronchial Provocation Tests; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism*; D005786:Gene Expression Regulation; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism; D008171:Lung Diseases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D017385:Sequence Homology; D063268:Sialic Acid Binding Ig-like Lectin 3; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D013601:T-Lymphocytes / Q000378:metabolism
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D063268:Sialic Acid Binding Ig-like Lectin 3; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C443130:Siglecf protein, mouse; D019158:N-Acetylneuraminic Acid