Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation

Abstract

Inflammatory response induced by microglia plays a critical role in the demise of neuronal populations in neuroinflammatory diseases. Although the role of toll-like receptor 4 (TLR4) in microglia's inflammatory response is fully acknowledged, little is known about endogenous ligands that trigger TLR4 activation. Here, we report that galectin-3 (Gal3) released by microglia acts as an endogenous paracrine TLR4 ligand. Gal3-TLR4 interaction was further confirmed in a murine neuroinflammatory model (intranigral lipopolysaccharide [LPS] injection) and in human stroke subjects. Depletion of Gal3 exerted neuroprotective and anti-inflammatory effects following global brain ischemia and in the neuroinflammatory LPS model. These results suggest that Gal3-dependent-TLR4 activation could contribute to sustained microglia activation, prolonging the inflammatory response in the brain.

Lack of galectin-3 improves the functional outcome and tissue sparing by modulating inflammatory response after a compressive spinal cord injury

“…Several studies using different experimental models, have indicated that galectin-3 plays a key role in recruitment and activation of neutrophils, monocytes, macrophages and microglia, and its absence leads to a decrease in recruitment of inflammatory cells to the injured tissue and their activation in it (Alves et al, 2010;Farnworth et al, 2008;Jiang et al, 2009;Nieminen et al, 2005;Rotshenker, 2009;Rotshenker et al, 2008). Nowadays, there is a growing body of evidence demonstrating the importance of this protein after pathologic, inflammatory and traumatic injuries to the CNS (Burguillos et al, 2015;Jiang et al, 2009;Manouchehrian et al, 2015;Pajoohesh-Ganji et al, 2012) however, up to now there are no reports in the literature describing the spatiotemporal changes after SCI in the absence of galectin-3.…”

“…MacKinnon et al (2008) showed that galectin-3 RNA inhibition in macrophages, blocked the alternative macrophage activation mediated by IL-4, while the classical activation mediated by IFN-γ and bacterial membrane lipopolysaccharide (LPS), was not affected . In a recent manuscript, Burguillos et al (2015) demonstrated, in vitro and in vivo, that galectin-3 has a strong effect on microglial cell activation through interaction with Toll-like 4 receptors (TLR4), inducing these cells to express pro-inflammatory molecules. Differing from the observations of MacKinnon et al (2008), they found that the inhibition of galectin-3 facilitates macrophage polarization into M2 phenotypes in vitro.…”

“…Differing from the observations of MacKinnon et al (2008), they found that the inhibition of galectin-3 facilitates macrophage polarization into M2 phenotypes in vitro. Furthermore, their in vivo observations demonstrated that Gal-3 −/− mice presented a lower macrophage influx and microglial reactivity after LPS injection in the substantia nigra (Burguillos et al, 2015).…”

Re‐wiring regulatory cell networks in immunity by galectin–glycan interactions

“…Interestingly, recent studies by Burguillos and colleagues elegantly showed that Gal-3 serves as an endogenous paracrine ligand for TLR4 on microglia cells, shifting the balance toward an M1-type phenotype, which accentuates CNS inflammation [135]. In accordance with these findings, cuprizone (CPZ)-treated mice displayed heightened M1 microglial activation associated with ectodermal dysplasia protein 1 (ED1) expression and pronounced upregulation of the phagocytic triggering receptor expressed on myeloid cells 2 (TREM-2b), while this effect was not observed in CPZ-treated Lgals3 À/À mice [136].…”

Early Hyperbaric Oxygen Treatment Attenuates Burn-Induced Neuroinflammation by Inhibiting the Galectin-3-Dependent Toll-Like Receptor-4 Pathway in a Rat Model

“…A recent study reported that galectin-3 (Gal-3)-TLR-4 interaction is related to neuroinflammation in a mouse model [18]. Currently, 14 mammalian galectins have been reported, and they can be divided into three groups: prototype (Gal-1, -2, -5, -7, -10, -11, -13, and -14), chimera (Gal-3), and tandem repeat (Gal-4, -6, -8, -9, and -12).…”