The various mechanisms by which galectins can regulate adaptive and innate immune responses

In a recent review published in Journals Nature Immunologyresearchers explored the ways in which galectins may impact immunity and discussed the opportunities and challenges in this area.

Background

Galectins include carbohydrates or glycan-binding proteins that are expressed by several cell types and bind to galactose-containing glycans. Galectin molecules can be located in the cytoplasm or nucleus or can be secreted extracellularly. They can modulate innate and adaptive immunological responses dependent or independent of carbohydrate-based interactions.

In the present review, researchers explored galectin-mediated immunological regulation.

Galectin molecules as unique regulators of host immune response

Galectins can be classified into chimeric type, tandem repeat type and prototypical galectins based on their structures. Importantly, glycan adjustments in cell surface proteins could be altered after cell activation and differentiation, resulting in engagement of galectins from different glycolipid or glycoprotein targets and, therefore, results different signaling pathways.

Among immunological cells (innate immunological cells, including dendritic cells and macrophages, and adaptive immunological cells, including B lymphocytes and T lymphocytes), immunological interactions could affect cell activation, cytokine secretion, chemotaxis and cell fate.

Galectins are present or secreted in the cytoplasm but can also be localized in the nucleus. Cytoplasmic galectins could affect cell signaling by being directly linked to intracellular molecular targets, including ALIX (protein X interacting with ALG2) and BCL-2 (protein B-cell lymphoma-2) via glycan-independent interactions. The interactions could affect cell survival, autophagy and phagocytosis. Galectins located at the intracellular level can bind to carbohydrates exposed as a result of organelle damage, which induces autophagy.

Adaptive modulation of the immunological response by galectin molecules

Galectin molecules can regulate adaptive immunological cells via extracellular and intracellular mechanisms and effects on APCs (antigen-presenting cells) and other cells of the innate immune system. Galectin-3 proteins located outside the cell can regulate T-cell activation by engaging extracellular carbohydrates on the differentiation coreceptor cluster (CD8) and other glycoconjugates that limit the CD8-TCR (T-cell receptor) and class I CD8-MHC (major histocompatibility complex) interactions at the immunological synapse.

Restriction of CD8 activity is regulated by MGAT5 (β1,6-N-acetylglucosaminyltransferase V), an enzyme induced by interleukin-10 (IL-10) that catalyzes the production of N-glycan molecules with ligands of polylactosamine type of galectin. The intracellularly located protein galectin-3 could increase the TCR activation threshold, and galectin-9 showed opposite effects.

A defect in T cell contraction was observed in murine knockout animals for galectin-1, galectin-8 and galectin-9 after challenge, with T cell apoptosis after administration of extracellular galectin-1, galectin-2, galectin-3, galectin-8 and galectin-9. Additionally, intracellularly located galectin-3 induces T cell apoptosis via BCL-2 interactions.

Galectins may also regulate B cell differentiation via extracellular and probably intracellular pathways. For example, B cells knocked out of the protein galectin-3 showed an increased propensity to differentiate to form plasma cells and germinal center (GC) B cells that secrete immunoglobulin G3 (IgG3) or IgG2c, which which can increase the risk of autoimmunity.

The galectin-9 protein can cause transmembrane protein CD-22,45-BCR (B cell receptor) interactions and a consequent decrease in BCR signaling. In contrast, B cells present in germinal centers secrete carbohydrate antigen I which decreases inhibition of B cell signaling mediated by galectin-9 and CD-22,45 and increases B cell responses to antigen exposure.

Regulation of macrophages by intracellular and extracellular galectins

Galectins can affect macrophage polarization, phagocytosis, and inflammasome activation. For example, galectin-3 is induced among cardiac macrophages in models of myocardial infarction, where it promotes their polarization into M2-type macrophages, contributing to tissue repair by promoting fibrosis and clearance of apoptotic cells after a myocardial infarction. Galectin-3 expression is induced via activation of STAT3 (signal transducer and activator of transcription 3).

IL-4 also induces galectin-3 expression, and galectin-3 facilitates polarization of M2-like macrophages by binding to CD98, which induces PI3K (phosphoinositide-3-kinase). Galectin-12 is also expressed by myeloid cells and upregulates M1 macrophage polarization in response to LPS (lipopolysaccharide) treatment in relation to lower NF-κB (nuclear factor kappa B) activation and M1 polarization which results. In addition, intracellular galectin-3 upregulates NLRP3 (NLR family pyrin domain containing 3) inflammasome, macrophage phagocytosis and actin rearrangement.

Galectins as sensors of endolysosomal lesions

Cellular organelles can be disrupted by intracellular bacteria that secrete toxins into cells. Lysosomal damage can be induced by LLOMe (Leu-Leu-O-Me) and GPN (glycyl-l-phenylalanine 2-naphthylamide). Since galectin can bind to signaling molecules through non-carbohydrate interactions, this can result in the formation of a “signaling platform”, induction of autophagic activation and bacterial killing.

Galectins-3 and -8 bind to β-galactosides exposed on damaged membranes are associated with TRIM16 (Protein containing a tripartite unit 16), and trigger autophagy. Galectin-8 activates autophagy mechanisms by inactivating mTOR (mammalian target of rapamycin). Galectin-9 binds to glycoproteins on damaged lysosomes leading to inhibition of USP9X, activation of TAK1 (transforming growth factor – β – activated kinase 1) and AMPK (AMP-activated protein kinase) and autophagy.

Conclusion

Based on the results of the review, galectins can modulate immunological cell functions by binding to major cell surface receptors. However, further research is needed to validate the functions and mechanisms of galectin and to investigate the potential therapeutic significance of the proteins.