Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology

Abstract

Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene α, interleukin (IL)-10, IL-7, transforming growth factor β1 and tumor necrosis factor-α, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential roles for Siglec-11 in ovarian physiology and human evolution.

Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes

“…The CD33-related siglecs are a family of evolutionarily non-conserved genes with unique expression patterns observed in humans151617181940414243, and even chimpanzees do not express all the same Siglecs1843. In confirmation with such previous data, we found the siglec functional paralogs absent in mouse endocrine cells.…”

“…Most siglecs are differentially expressed on hematopoietic and immune cells. So far, the exceptions are, Siglec-4 (myelin-associated glycoprotein, MAG) on glial cells14, Siglec-5 and 14 on human amniotic epithelium15, Siglec-6 on the human placental trophoblast16, Siglec-11 on ovarian fibroblasts17 and Siglec-12 on certain hominid epithelial cells1819.…”

Evolution of genetic and genomic features unique to the human lineage

“…Siglec-11 expression alleviates neurotoxicity of microglial cells, which can damage neurons and contribute to neurodegenerative disorders 86 . More recently, a unique expression pattern of Siglec-11 and its ligands in human ovaries has demonstrated a possible role in HLS ovarian changes 111 .…”

Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs

“…properly posttranslationally modified PSGL-1 (52). Similarly, there are also CD33rSiglecs that recognize a narrow spectrum of ligands, such as Siglec-11 (53).…”