Siponimod inhibits disease-associated microglia-T cell interactions in chronic experimental autoimmune encephalomyelitis

Chronically inflamed, reactive microglia represent a prominent feature of secondary progressive multiple sclerosis (SPMS). Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the treatment of active SPMS, to inhibit disease-associated T cell-microglia interactions using a chronic murine experimental autoimmune encephalomyelitis (EAE) model of MS. We found that therapeutic siponimod treatment of chronic EAE improved clinical severity accompanied by reduced demyelination and neuroaxonal damage, diminished CNS T cell infiltration and altered proinflammatory microglia responses. This effect was partly attributed to a direct effect on microglia, as siponimod pretreatment inhibited interferon-γ-elicited responses of primary mouse microglia in vitro and limited their ability to induce T cell activation and proliferation in T cell-microglia co-cultures. Additionally, we observed reduced peripheral T cell numbers in our EAE model, with a pronounced shift to immunosenescent and regulatory T cell subsets, a pattern which we similarly detected in a cohort of SPMS patients following siponimod treatment. These findings indicate that siponimod dampens compartmentalized CNS inflammation by disrupting detrimental interactions between T cells and microglia through a dual central and peripheral mechanism of action.