Inflammatory demyelinating diseases comprise a diverse group of disorders where multiple sclerosis (MS) is the most prevalent one. Currently, immunomodulatory strategies slow disease progression but fail to stop inflammation-driven neurodegeneration and counteract the demyelination process. Hence, a better understanding of immunoregulatory mechanisms controlling MS is needed to discover novel targets and develop effective treatments.
In MS patients, the cation channel TMEM176B - an inflammasome inhibitor - has been associated with clinical responses to immunomodulatory therapy. Here, we hypothesized that TMEM176B may control progression of autoimmune encephalomyelitis.
Using the EAE model, we observed Tmem176b-/- mice had an increased disease severity compared to WT and Tmem176b-/-Caspase-1-/- animals, outlining a role for inflammasomes in severe disease of Tmem176b-/- mice. Accordingly, spinal cords from Tmem176b-/- showed an increase in active Caspase-1 and microgliosis, versus WT animals. Mechanistically, we observed that TMEM176B is regulated by the immunoregulatory lectin Galectin-1. Galectin-1 interacts with TMEM176B, and inhibits the inflammasome in a Tmem176b-dependent manner in human macrophages and mouse dendritic cells. Accordingly, Galectin-1 triggers TMEM176B ion-transport function. In humans, the TMEM176B Single Nucleotide Polymorphism (SNP) rs2072443 (A134T substitution) has been associated with increased inflammasome activation. Accordingly, we observed a complete loss-of-function in the mutant protein. Thus, A134T TMEM176B leads to impaired ion-transport and fails to control inflammasome activation. Intriguingly, impaired ion-transport could be recovered using Galectin-1. Current experiments are being designed to investigate the potential association between TMEM176B SNP rs7022443 and MS severity. Our results support TMEM176B as a druggable host factor controlling autoimmune encephalomyelitis.
