Microglia-derived galectin-3 in neuroinflammation; a bittersweet ligand?

Galectins are soluble β-galactoside-binding proteins found in all multicellular organisms. Galectins may act as danger-associated molecular patterns in innate immunity and/or as pattern-recognition receptors that bind to pathogen-associated molecular patterns. Among different galectin family members, galectin-3 has been the focus of studies in neurodegenerative diseases in recent years. This lectin modulates brain innate immune responses, microglia activation patterns in physiological and pathophysiological settings in a context-dependent manner. Galectin-3 is considered as a pivotal tuner of macrophage and microglial activity. Indeed galectin-3 acts as a double edged sword in neuroinflammatory context and this multimodal lectin has diverse roles in physiological and pathophysiological conditions. Better understanding of galectin-3 physiology (its extracellular and intracellular actions) and structure (its C terminus vs. N terminus) is instrumental to design molecules that selectively modulate galectin-3 function toward neuroprotective phenotypes. Several experimental studies using different approaches and methods have demonstrated both protective and deleterious effects of galectin-3 in neuroinflammatory diseases. According to the crucial role of galectin-3 in modulation of innate immune response in brain, it is an attractive target in drug discovery of neurodegenerative diseases. The current insight attempts to provide an updated and balanced discussion on the role of galectin-3 as a complex endogenous immune modulator. This helps to have a better insight into the development of galectin-3 modulators with translational value in different neurological disorders including stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and Parkinson's disease.