Siponimod inhibits microglial inflammasome activation

Siponimod is the first oral drug approved for active secondary progressive multiple sclerosis. It acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P₁) through S1P₁ internalization, and also serves an agonist of S1P₅; however, the detailed mechanisms of its therapeutic effects on glial cells have yet to be elucidated. In this study, we investigated the anti-inflammatory mechanism of siponimod in microglia. Pretreatment with either siponimod or the S1P₁ antagonist W146 significantly suppressed the production of interleukin-1β in activated microglia stimulated with lipopolysaccharide plus nigericin, an inflammasome activator. Furthermore, siponimod treatment reduced the protein levels of cleaved Caspase-1 and inhibited the formation of aggregates of apoptosis-associated speck-like protein containing a C-terminal Caspase recruitment domain (ASC specks) in microglia. Our data indicate that siponimod achieves its anti-inflammatory effects by inhibiting inflammasome activation in microglia via S1P₁ antagonism. This process is inferred to play a crucial role in mitigating the secondary progression of multiple sclerosis, where microglial activation in the gray matter is considered a key pathological factor.