Colonic Epithelial Cells Express Specific Ligands for Mucosal Macrophage Immunosuppressive Receptors Siglec-7 and -9

Abstract

Immune cells are known to express specific recognition molecules for cell surface glycans. However, mechanisms involved in glycan-mediated cell–cell interactions in mucosal immunity have largely been left unaccounted for. We found that several glycans preferentially expressed in nonmalignant colonic epithelial cells serve as ligands for sialic acid-binding Ig-like lectins (siglecs), the immunosuppressive carbohydrate-recognition receptors carried by immune cells. The siglec ligand glycans in normal colonic epithelial cells included disialyl Lewisa, which was found to have binding activity to both siglec-7 and -9, and sialyl 6-sulfo Lewisx, which exhibited significant binding to siglec-7. Expression of these siglec-7/-9 ligands was impaired upon carcinogenesis, and they were replaced by cancer-associated glycans sialyl Lewisa and sialyl Lewisx, which have no siglec ligand activity. When we characterized immune cells expressing siglecs in colonic lamina propriae by flow cytometry and confocal microscopy, the majority of colonic stromal immune cells expressing siglec-7/-9 turned out to be resident macrophages characterized by low expression of CD14/CD89 and high expression of CD68/CD163. A minor subpopulation of CD8+ T lymphocytes also expressed siglec-7/-9. Siglec-7/-9 ligation suppressed LPS-induced cyclooxygenase-2 expression and PGE2 production by macrophages. These results suggest that normal glycans of epithelial cells exert a suppressive effect on cyclooxygenase-2 expression by resident macrophages, thus maintaining immunological homeostasis in colonic mucosal membranes. Our results also imply that loss of immunosuppressive glycans by impaired glycosylation during colonic carcinogenesis enhances inflammatory mediator production.

Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer

“…Previous analysis also identified Siglec-7 and -9 ligands present in colorectal cancer and also found a role for those Siglecs in the generation of tumor-associated macrophages (43). Moreover, inhibitory Siglecs, including Siglec-7 and, in a minor fraction, Siglec-9, are expressed on NK cells (6,44).…”

Identification of CD68+ neutrophil granulocytes in in vitro model of acute inflammation and inflammatory bowel disease

“…If the CD-68 antigen is not expressed solely in macrophages but also by NGs, the finding of MPO in CD-68 + cells is explained. This is important especially when physiology of intestinal immune system is studied [17].…”

Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance

“…Knowledge about Siglec expression and function on NK cell subsets is still limited in terms of NK cell differentiation and maturation, and the role of Siglec ligand-receptor interactions in disease remains to be explored. Whether Siglec-7 and -9 ligands in human cancer are expressed on malignant or healthy cells is a subject of controversy (3,(25)(26)(27)(28), as is the related question as to whether absence of inhibitory Siglecligand interactions promotes or inhibits tumor progression, either by uncoupled immune stimulation or by inhibition of immune defense (10,(25)(26)(27). Here, we found that Siglec-7 and -9 ligands were significantly overexpressed on a broad range of human malignant cells of different histological types and that surface Siglec-7 and -9 ligand expression determined cytotoxicity of human primary NK cells against both NK cell-susceptible and -resistant tumor cells.…”