Galectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases

Abstract

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of β-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

Keywords: Galectin-3; central nervous system diseases; chronic pain; galectin-3 inhibitor; microglia; neuroinflammation.

Fig. (1)

The effects and underlying mechanisms of Gal-3 in the activation of immune cells in various diseases. AKT: protein kinase B; ERK: extracellular signal-regulated kinase; IL-1β: interleukin-1 beta; IL-4: interleukin-4; LPS: lipopolysaccharide; JNK1: c-Jun N-terminal kinase 1; MAPK: mitogen-activated protein kinase; PI3K: phosphatidylinositide 3-kinases; PKC: protein kinase C; ROS: reactive oxygen species. The figure was created using BioRender.com.

Fig. (2)

Signaling mechanisms of Gal-3 involved in microglia-mediated proliferation, neuroinflammation, and phagocytosis in CNS diseases. (1) Secreted Gal-3 involved in microglia-mediated myelin phagocytosis via regulating K-Ras-GTP-dependent PI3K activity. Moreover, Gal-3 could also bind to MerTK or interact with TREM2/DAP12 signaling, thus regulating microglia-mediated phagocytosis. (2-3) Gal-3 could interact with TREM2/DAP12 signaling, participating in various biological processes, including DAM activation or microglial proliferation. (4) Gal-3 could also bind to IGFR and is involved in the IGF-1-mediated proliferation of microglia. (5) Gal-3 released by activated microglia could directly interact with TLRs or TREM2, thus exacerbating the release of inflammatory factors. DAM: microglia phenotype associated with neurodegenerative diseases; DAP12: DNAX-activating protein of 12 kDa; Gal-3: galectin-3; IGF-1: insulin-like growth factor 1; IGF-R1: insulin-like growth factor receptor 1; JNK: c-Jun N-terminal kinase; MerTK: Mer tyrosine kinase; NF-κB: nuclear factor-κB; PI3K: phosphatidylinositide 3-kinases; STAT3: signal transducer and activator of transcription 3; TLRs: Toll-like receptors; TREM2: triggering receptor expressed on myeloid cell 2. The figure was created using BioRender.com.

Fig. (3)

The underlying mechanisms of Gal-3 that participate in the development of different types of pathological pain. (1) The possible mechanisms of Gal-3 that participate in the development of HZ-induced neuropathic pain. (2) Gal-3 inhibition could remarkably suppress SNL-induced neuroinflammation and neuropathic pain, at least in part via regulating autophagy activation. (3) Gal-3 plays a crucial role in aggravating the neuroinflammation of SCI rats via regulating the activation of the ROS/TXNIP/NLRP3 signaling pathway. Inhibition of Gal-3 improved the functional recovery of SCI rats via regulating the polarization of microglia towards the M2 phenotype. (4) Overexpression of miR-185 suppresses IDD-induced apoptosis and cell autophagy through suppression of the Wnt/β-catenin signaling pathway via regulating Gal-3. ERK: extracellular signal-regulated kinase; Gal-3: galectin-3; HZ: herpes zoster; IDD: intervertebral disc degeneration; LC-3: microtubule-associated protein 1 light chain 3; NLRP3: nod-like receptor protein 3; ROS: reactive oxygen species; SCI: spinal cord injury; SNL: spinal nerve ligation; TLR-4: Toll-like receptor-4; Trx: thioredoxin; TXNIP: thioredoxin-interacting protein. The figure was created using BioRender.com.