Galactins bind specifically to β-galactoside through an evolutionarily conserved sequence element of the carbohydrate recognition domain (CRD). The unique member of the family is galectin-3. In addition to CRD, it also contains proline and a glycine-rich N-terminal domain (ND) through which oligomers can be formed.
Structural and Biochemical Characteristics
Galectin-3 is a secretory protein of ~30 kDa and belongs to a family of β-galactoside-binding animal lectins. In contrast to FcεRI and CD23, galectin-3 does not exist as a transmembrane protein. The structure of galectin-3 consists of a CRD linked to a non-lectin region of proline- and glycine-rich tandem repeats. Similar to all other galectin family members, galectin-3 lacks a classical signal for the secretory pathway. Galectin-3 resides in the cytosol or the nucleus, but has also been shown to associate with intracellular vesicles and has been found in exosomes from dendritic cells. Galectin-3 expression appears to be species-specific and differences between humans and mice are described. Similar to FcεRI, galectin-3 was found on humans but not murine eosinophils. Galectin-3 might thus be another IgE Fc-receptors for which species-specific expression patterns might hamper interpretation of murine studies.
Fig.1 Galectin family classification and structure of galectin-3. (Tan, 2021)
Galectin-3 as A Biomarker
Elevated serum levels of galectin-3 are found in many diseases including various types of autoimmune diseases and cancer. So far, the only FDA-approved application of galectin-3 as a biomarker is for the prognosis of chronic heart failure. However, galectin-3 has recently emerged also as a promising diagnostic marker for thyroid cancers.
Functions of The Soluble IgE Receptor Galectin-3 in The IgE Network
Galectin-3 is a versatile player of the immune system. Secreted galectin-3 can activate cells directly by binding to cell surface receptors. Alternatively, galectin-3 is endocytosed, permitting it to modify intracellular signaling pathways. A large number of intracellular as well as extracellular galectin-3 binding partners, therefore, allows this protein to play a role in a large variety of inflammatory responses. In the context of allergic reactions, it is important to note that extracellular galectin-3 is a potent activator of mast cells via crosslinking of IgE-loaded FcεRI or via crosslinking FcεRI directly in an IgE-independent manner. Galectin-3 was shown to induce inflammatory mediator release from IgE-sensitized as well as non-sensitized mast cells and human eosinophils.
Possible Role in Periodontal Diseases and Potential Therapeutic Target
By direct binding to microbes and modulation of their clearence, Galectin-3 can affect the composition of the microbial community in the oral cavity. Galectin-3 also modulates the function of many immune cells in the gingiva and gingival sulcus and thus can affect immune homeostasis. Therapeutic effects of Gal-3 inhibition in bacteria induced PBC and DSS induced colitis where intestinal microbiota contribute to disease pathogenesis indicate possible positive effects of Gal-3 inhibition in periodontitis. Recently, Gal-3 binding core-shell glyconanoparticles based on citrus pectin, with Gal-3 inhibition properties, have been designed for targeted and combination drug delivery.
Fig.2 Possible role of Gal-3 in the development of periodontal diseases by modulation of the key players in periodontitis pathogenesis. (Velickovic, 2021)
Galectin-3 Antagonists for Cancer Therapy
Tumor cells released galectin-3 was found to bind glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein-galectin lattices that could reduce the motility and functionality of TILs. Disruption of glycoprotein-galectin-3 lattices using anti-galectin-3 antibodies, or galectin-3 antagonists such as N-acetyllactosamine, GCS-100 (MCP-derived polysaccharide), or GM-CT-01 (a galactomannan from guar gum) boosted cytokine secretion by TIL. Moreover, the purified TFD compound also blocked T-cell apoptosis mediated by either recombinant, tumor-associated, or cancer patient serum-associated galectin-3.
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References
- Tan, Y.; et al. Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease. Cell & Bioscience. 2021, 11(1): 1-13.
- Velickovic, M.; et al. Galectin-3, Possible Role in Pathogenesis of Periodontal Diseases and Potential Therapeutic Target. Frontiers in Pharmacology. 2021, 12.
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