Siglec-8

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Siglec-8 is a human siglec expressed predominantly on eosinophils and mast cells, and is a paradigm for the rapidly evolving sub-family of CD33-related siglecs that are expressed on various white blood cells[1] [2] [3] [4]. A characteristic feature of Siglec-8 and most other CD33-related siglecs is a cytoplasmic domain with a single immunoreceptor tyrosine inhibitory motif (ITIM) and a single ITIM-like motif that participate in siglec-mediated regulation of cell signaling and endocytosis. While there is no clear ortholog in mice, Siglec-F has been documented as a functional paralog that has a similar expression pattern on murine leukocytes and similar ligand specificity[3][5] [6]. Siglec-8, and its murine paralog Siglec-F, recognize a ligand containing both sialic acid and sulfate (NeuAcα2-3[6S]Galβ1-4G[Fucα1-3]GlcNAc-), a specificity that is distinct from all other siglecs. Ligation of Siglec-8 (or Siglec-F) with antibodies or polymeric ligands induces apoptosis of eosinophils, suggesting a therapeutic approach for treating eosinophil (or mast cell) mediated disease by targeting Siglec-8[7][8] [9] [10].

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

Participating Investigators (PIs) of the CFG have made major contributions to the understanding of the biology of Siglec-8 and its murine paralog, Siglec-F. These include: Bruce Bochner, Nicolai Bovin, Paul Crocker, James Paulson, Ronald Schnaar, Ajit Varki

Progress toward understanding this GBP paradigm

Carbohydrate ligands

The high affinity ligand for Siglec-8 has been deduced from glycan microarray screening on the CFG microarray[1][2] to be NeuAcα2-3(6-SO3)Galβ1-4(Fucα1-3)GlcNAc [6'Su-SLeX] [9][5]

File:6pso3slex.jpg

For Siglec-F, histologic studies suggest the presence of an α2,3-linked sialylated glycoprotein ligand expressed by airway epithelium. Its constitutive expression requires the enzyme St3Gal3.[11] Levels of this ligand are increased during allergic pulmonary inflammation. [6]

Cellular expression of GBP and ligands

Siglec-8 is expressed in human eosinophils, mast cells, and basophils (weakly). [2] [4][12]

Biosynthesis of ligands


Structure

File:Siglec8 SiglecF.jpg

Biological roles of GBP-ligand interaction

In vitro Eosinophil apoptosis. [10][13][14] Inhibition of mast cell mediator release.[15]

In vivo (for Siglec-F) Antibody administration to mice causes selective depletion of eosinophils in blood and gastrointestinal tissues via apoptosis.[16] They are also effective in reversing some sequelae of mouse models of eosinophilic gastroenteritis and asthma.[17][18]

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for Siglec-8.

Glycan profiling

Glycan structure analysis has been conducted by the CFG for human[3] and mouse[4] eosinophils.

Glycogene microarray

Analysis has been conducted on glycosyltransferase expression using the glycogene microarray for murine eosinophils that relates to the enzymes required for expression of cis ligands of Siglec-F on these cells[5].

Knockout mouse lines

Mice deficient in Siglec-F have normal blood and bone marrow eosinophils at baseline, but develop exaggerated bone marrow, blood and lung eosinophilia after allergen sensitization and challenge. [6]

Glycan array

The discovery of the ligand for Siglec-8[6][7] and its murine paralog, Siglec-F[8][9], was made by investigator-initiated resource requests for glycan array analysis and carbohydrate compounds. To see all glycan array results for Siglec-8, click here.

Related GBPs

hSiglec-3 (CD33), Siglec-5, Siglec-6, Siglec, 7, Siglec-9, Siglec-10, Siglec-11, Siglec-F, Siglec-E, Siglec-G

References

  1. Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266 (2007).
  2. 2.0 2.1 Kikly, K.K., Bochner, B.S., et al. Identification of SAF-2, a novel siglec expressed on eosinophils, mast cells, and basophils. J Allergy Clin Immunol 105, 1093-100 (2000)
  3. 3.0 3.1 Bochner, B.S. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin Exp Allergy 39, 317-324 (2009).
  4. 4.0 4.1 Floyd H, Ni J, Cornish AL, Zeng Z, Liu D, Carter KC, Steel J, Crocker PR. Siglec-8: a novel eosinophil-specific member of the immunoglobulin superfamily. J Biol Chem 2000; 275:861-6.
  5. 5.0 5.1 Tateno, H., Crocker, P. R. & Paulson, J. C. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred glycan ligand. Glycobiology 15, 1125-1135 (2005).
  6. 6.0 6.1 6.2 Zhang M, Angata T, Cho JY, Miller M, Broide DH, Varki A. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils. Blood 2007; 109:4280-7
  7. O'Reilly, M. K. & Paulson, J. C. Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 30, 240-248 (2009).
  8. Zimmermann, N. et al. Siglec-F antibody administration to mice selectively reduces blood and tissue eosinophils. Allergy 63, 1156-1163 (2008).
  9. 9.0 9.1 Bochner, B. S. et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 280, 4307-4312 (2005).
  10. 10.0 10.1 Nutku, E., Aizawa, H., Hudson, S. A. & Bochner, B. S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis. Blood 101, 5014-5020 (2003).
  11. Guo JP, Brummet ME, Myers AC, Na HJ, Rowland E, Schnaar RL, Zheng T, Zhu Z, Bochner BS. Characterization of expression of glycan ligands for Siglec-F in normal mouse lungs. Am J Respir Cell and Molec Biol 2010 Apr 15 [Epub ahead of print] 2010 and
  12. Yokoi H, Myers A, Matsumoto K, Crocker PR, Saito H, Bochner BS. Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells. Allergy 2006; 61:769-76
  13. Nutku E, Hudson SA, Bochner BS. Mechanism of Siglec-8-induced human eosinophil apoptosis: role of caspases and mitochondrial injury. Biochem Biophys Res Commun 2005; 336:918-24
  14. 1Nutku-Bilir E, Hudson SA, Bochner BS. Interleukin-5 priming of human eosinophils alters Siglec-8 mediated apoptosis pathways. Am J Respir Cell Mol Biol 2008; 38:121-4
  15. Yokoi H, Choi OH, Hubbard W, Lee H-S, Canning BJ, Lee HH, Ryu S-D, Bickel CA, Hudson SA, MacGlashan DW, Jr., Bochner BS. Inhibition of FcεRI-dependent mediator release and calcium flux from human mast cells by Siglec-8 engagement. J Allergy Clin Immunol 2008; 121:499-505
  16. Zimmermann N, McBride ML, Yamada Y, Hudson SA, Jones C, Cromie KD, Crocker PR, Rothenberg ME, Bochner BS. Siglec-F antibody administration to mice selectively reduces blood and tissue eosinophils. Allergy 2008; 63:1156-63
  17. Song DJ, Cho JY, Miller M, Strangman W, Zhang M, Varki A, Broide DH. Anti-Siglec-F antibody inhibits oral egg allergen induced intestinal eosinophilic inflammation in a mouse model. Clin Immunol 2009; 131:157-69
  18. Song DJ, Cho JY, Lee SY, Miller M, Rosenthal P, Soroosh P, Croft M, Zhang M, Varki A, Broide DH. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J Immunol 2009; 183:5333-41

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Bruce Bochner, Paul Crocker, James Paulson, Ron Schnaar

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