Diverse mechanisms by which galectins regulate adaptive and innate immune responses

In a recent review published in nature review immunologyresearchers investigated how galectins influence immunity and discussed the opportunities and challenges in this area.

Background

Galectins are expressed by several types of cells and contain carbohydrate or glycan-binding proteins that bind galactose-containing glycans. Galectin molecules are located in the cytoplasm or nucleus or are secreted extracellularly. They can modulate innate and adaptive immune responses either dependently or independently of carbohydrate-based interactions.

In the current review, researchers investigated galectin-mediated immunological regulation.

Galectin molecules as intrinsic host immune response regulators

Galectins are classified into chimeric, tandem repeat, and prototypical galectins based on their structures. Importantly, glycan regulation of cell surface proteins can change after cell activation and differentiation, resulting in the involvement of different glycolipid or glycoprotein targets of galectins and different outcomes of signaling pathways. increase.

Immunological interactions between immune cells (innate immune cells such as dendritic cells and macrophages, adaptive immune cells such as B and T lymphocytes) are responsible for cell activation, cytokine secretion, chemotaxis, May affect cell fate.

Galectins are present or secreted in the cytoplasm, but may also be present in the nucleus. Cytoplasmic galectins bind directly to intracellularly located molecular targets such as ALIX (ALG2-interacting protein X) and BCL-2 (B-cell lymphoma protein-2) through glycan-independent interactions. , which can affect cell signaling. Interactions can affect cell survival, autophagy and phagocytosis. Intracellularly located galectins can bind to exposed carbohydrates following organelle injury to induce autophagy.

Regulation of adaptive immune responses by galectin molecules

Galectin molecules can modulate adaptive immune cells through extracellular and intracellular mechanisms and effects on APCs (antigen-presenting cells) and other cells of the innate immune system. Extracellularly located galectin-3 proteins regulate T lymphocyte activation by engaging extracellular carbohydrates with CD8-TCR-restricting differentiation (CD8) co-receptors and clusters of other glycoconjugates can (T cells receptor) interactions and CD8-MHC (major histocompatibility complex) interactions at class I immunological synapses.

Limitation of CD8 activity is regulated by the interleukin-10 (IL-10)-inducible enzyme MGAT5 (β1,6-N-acetylglucosaminyltransferase V), which regulates N by polylactosamine-type ligands of galectins. -Catalyzes the production of glycan molecules. Intracellularly located galectin-3 proteins can raise the TCR activation threshold, and galectin-9 has shown the opposite effect.

Defects in T lymphocyte contractility have been observed among post-challenge galectin-1, galectin-8, and galectin-9 knockout mouse animals, with T lymphocyte contractility following administration of extracellular galectin-1, galectin-2, and galectin-3. Cellular apoptosis has been observed. galectin-8, galectin-9. Furthermore, intracellularly located galectin-3 induces T lymphocyte apoptosis through BCL-2 interaction.

Galectins can also regulate B lymphocyte differentiation through extracellular and possibly intracellular pathways. For example, galectin-3 protein knockout B lymphocytes show an increased propensity to differentiate to form immunoglobulin G3 (IgG3) or IgG2c-secreting plasma cells and germinal center (GC) B lymphocytes and are self-representative. May increase immunity potential.

Galectin-9 protein can trigger CD-22,45 transmembrane protein-BCR (B cell receptor) interactions, resulting in decreased BCR signaling. In contrast, B lymphocytes residing in germinal centers secrete carbohydrate antigen I, reduce galectin-9 promotion and CD-22,45-mediated inhibition of B lymphocyte signaling, and increase B lymphocyte responses to antigen challenge. Let

Regulation of macrophages by intracellular and extracellular galectins

Galectins can influence macrophage polarization, phagocytosis and inflammasome activation. For example, galectin-3 is induced among cardiac macrophages in models of myocardial infarction, promoting their polarization to M2-like macrophages and contributing to tissue repair by promoting the clearance of fibrotic and apoptotic cells after myocardial infarction. Galectin-3 expression is induced through activation of STAT3 (signal transducer and activator of transcription 3).

IL-4 also induces the expression of galectin-3, which promotes polarization of M2-like macrophages by binding to CD98 which induces PI3K (phosphoinositide-3-kinase). Galectin-12 is also expressed in myeloid cells and is associated with reduced NF-κB (nuclear factor kappa B) activation and consequent M1 polarization in response to LPS (lipopolysaccharide) treatment and M1 macrophage polarization. actively adjust the Furthermore, intracellular galectin-3 positively regulates NLRP3 (Pyrin domains of the NLR family 3) including inflammasome, macrophage phagocytosis, and actin rearrangement.

Galectins as sensors of endolysosomal damage

Organelles can be destroyed by intracellular bacteria that secrete toxins into the cell. Lysosomal damage can be induced by LLOMe (Leu-Leu-O-Me) and GPN (glycyl-1-phenylalanine 2-naphthylamide). Given that galectins can bind signaling molecules through non-carbohydrate interactions, this may result in the formation of ‘signaling platforms’, induction of autophagy activation and destruction of bacteria.

Galectins-3 and -8 bind to exposed β-galactosides on injured membranes and associate with TRIM16 (tripartite motif-containing proteins 16), and induce autophagy. Galectin-8 activates the autophagic machinery by inactivating mTOR (mammalian target of rapamycin).Galectin-9 binds glycoprotein USP9X inhibition against damaged lysosomes leading to TAK1 activation (transforming growth factor-β-activated kinase 1) and AMPK (AMP-activated protein kinase), and autophagy.

Conclusion

Based on the review results, galectins can modulate immunological cell functions by binding to key cell surface receptors. However, further studies are needed to validate galectin functions and mechanisms and to explore the proteins’ potential therapeutic importance.