Galectin-9 Is a High Affinity IgE-binding Lectin with Anti-allergic Effect by Blocking IgE-Antigen Complex Formation

Abstract

Galectin (Gal)-9 was first described as an eosinophil chemoattractant. With the progress in research, Gal-9 has come to be known as a versatile immunomodulator that is involved in various aspects of immune regulations, and the entire picture of the function still remains elusive. To uncover as-yet unknown activity of Gal-9, we have been examining the effect of the protein in various disease animal models. Here we show that Gal-9 attenuated asthmatic reaction in guinea pigs and suppressed passivecutaneous anaphylaxis in mice. These results indicate the mast cell stabilizing effect of Gal-9. In vitro studies of mast cell degranulation involving RBL-2H3 cells demonstrated that Gal-9 suppressed degranulation from the cells stimulated by IgE plus antigen and that the inhibitory effect was completely abrogated in the presence of lactose, indicating lectin activity of Gal-9 is critical. We found that Gal-9 strongly and specifically bound IgE, which is a heavily glycosylated immunoglobulin, and that the interaction prevented IgE-antigen complex formation, clarifying the mode of action of the anti-degranulation effect. Gal-9 is expressed by several mast cells including mouse mast cell line MC/9. The fact that immunological stimuli of MC/9 cells augmented Gal-9 secretion from the cells implies that Gal-9 is an autocrine regulator of mast cell function to suppress excessive degranulation. Collectively, these findings shed light on a novel function of Gal-9 in mast cells and suggest a beneficial utility of Gal-9 for the treatment of allergic disorders including asthma.Galectin (Gal) 2 is a family of lectins characterized by a conserved carbohydrate recognition domain exhibiting binding specificity to ␤-galactoside (1). One of the members, Gal-9, has two carbohydrate recognition domains tethered by a linker peptide and is mainly expressed in the epithelium of the gastrointestinal tract and in immune cells (2-5). Gal-9, like other galectins, does not have a signal sequence and is localized in the cytoplasm. However, it is secreted into the extracellular milieu through poorly understood mechanisms and exerts biological functions by binding to the glycoproteins on the target cell surface via their carbohydrate chains.Two target glycoproteins of Gal-9 have been identified, namely T-cell immunoglobulin and mucin containing-protein 3 (TIM3) and CD44. TIM3 is expressed by several populations of immune cells including terminally differentiated Th1 cells and CD11b ϩ monocytes. Gal-9 stimulates cell death of TIM3 ϩ Th1 cells, leading to the termination of Th1-biased immunoreactions (6). On the other hand, Gal-9 promotes TNF␣ secretion from CD11b ϩ TIM3 ϩ monocytes and enhances innate immunity (7). CD44 is an important adhesion molecule for migrating lymphocytes and eosinophils. Gal-9 interaction with CD44 prevents CD44 from binding to hyaluronic acid, which is a principal ligand for CD44 and for providing a foothold for migrating cells; hence, attenuates accumulation of activated lymphocytes and eosinophils to the inflamed lesion (8)....

IgE immunotherapy

“…45 Galectin-9 binds to β-galactoside residues in the carbohydrate chains of IgE and can suppress allergic inflammation. 46 It exerts this activity by blocking the binding of antigens to IgE. Galectin-3 is secreted by epithelial cells and immune inflammatory cells and binds to carbohydrate chains containing β-galactoside residues.…”

Galectin-9: An anticancer molecule for gallbladder carcinoma

“…These two authors have the following patent related to material pertinent to this study: 'Novel modified galectin 9 proteins and use thereof' , which was applied for by GalPharma and was issued in Japan (4792390), the USA (8,268,324) …”

“…The functions of Gal-9 have been reported to include the induction of apoptosis in T-cells, particularly CD4 + Th1 and Th17 cells, and the stimulation of regulatory T-cell activity (5-7). Interestingly, Gal-9 has been tested as a potential therapeutic agent for various autoimmune diseases (7) and allergic diseases (8). Furthermore, it has been reported that Gal-9 suppresses the cell proliferation and tumor growth of various human cancer types (9,10), such as melanoma (11) and chronic myelogenous leukemia (12).…”

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

“…[52][53][54][55][56] Gal-9 engages with numerous cell surface receptors such as Tim-3, a variety of PDIs, and IgE. 45,57,58 The consequences of Gal-9 interactions with these diverse receptors are now being unraveled.…”