Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, Santiago M, Viceconte N, Oliva-Martin MJ, Osman AM, Salomonsson E, Amar L, Persson A, Blomgren K, Achour A, Englund E, Leffler H, Venero JL, Joseph B, Deierborg T. Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation. Cell Rep. 2015 Mar 4; PubMed.
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In this publication, Burguillos and colleagues have identified Galectin-3 (Gal3) as an endogenous ligand for Toll-like Receptor 4 (TLR4). The paper focuses on the microglia’s inflammatory response and the authors evaluated Gal3-mediated pro-inflammatory responses in the brain under conditions of acute brain inflammation. They observed neuroprotective and anti-inflammatory effects of Gal3 depletion following global brain ischemia and in the neuroinflammatory lipopolysaccharide model. They suggest that the inflammatory role of Gal3 in the brain may differ, depending on the specific neuroinflammatory conditions. Accordingly, a previous study (Lerman et al., 2012) showed that the deletion of Gal3 exacerbates microglial activation and accelerates disease progression and demise in an SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Thus the expression pattern and the biological effect of Gal3 in different neurological disorders characterized by activation of the TLR4 signaling pathway (such as epilepsy, ALS, and ALZ), should be further clarified using both experimental models and human tissue studies. Evaluation of the role of galectins as TLR4 ligands in different model and cell types (i.e. astrocytes) also requires further investigation.
Lerman BJ, Hoffman EP, Sutherland ML, Bouri K, Hsu DK, Liu FT, Rothstein JD, Knoblach SM. Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Brain Behav. 2012 Sep;2(5):563-75. PubMed.
I think this is a tantalizing study for two reasons. First, it demonstrates that Galectin-3 can directly interact with Toll-like Receptor 4 (TLR4). Second, since Gal3 is generally expressed and released exclusively by microglia within the brain following inflammation, Gal3 may play a role in “propagating” pro-inflammatory microglial responses by binding TLR4 on neighboring microglia. In a mouse model of Parkinson's disease (intrastriatal lipopolysaccharide injection), dopaminergic neurons were largely spared in Gal3 knockout mice, suggesting that normally Gal3 works to promote cell death in response to LPS. Given the authors' in vitro work, one might hypothesize that Gal3 works as an accelerator for widespread microglial activation in response to LPS. While further work is needed to conclusively demonstrate the paracrine nature of these effects (mixing experiments or mice in which Gal3 is not secreted), its implications are very interesting: Perhaps this system represents a mechanism by which small amounts of injury or inflammation can lead to widespread, prolonged, and possibly neurotoxic microglial activation in neurodegenerative diseases.
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